Process for the preparation of an oxirane, aziridine or cyclopropane

ABSTRACT

A process for the preparation of an oxirane, aziridine or cyclopropane of formula (I),                    
     wherein X is oxygen, NR 4  or CHR 5 ; R 1  is hydrogen, alkyl, aryl, heteroaromatic, heterocyclic or cycloalkyl; R 2  is hydrogen, alkyl, aryl, heteroaromatic, CO 2 R 8 , CHR 14 NHR 13 , heterocyclic or cycloalkyl; or R 1  and R 2  join together to form a cycloalkyl ring; R 3  and R 10  are, independently, hydrogen, alkyl, aryl, heteroaromatic, CO 2 R 8 , R 8   3 Sn, CONR 8 R 9 , trialkylsilyl or triarylsilyl; R 4  is an electron withdrawing group; R 5  is alkyl, cycloalkyl, aryl, heteroaromatic, SO 2 R 8 , SO 3 R 8 , COR 8 , CO 2 R 8 , CONR 8 R 9 , PO(R 8 ) 2 , PO(OR 8 ) 2  or CN; R 8  and R 9  are independently alkyl or aryl; and R 13  and R 14  are independently hydrogen, alkyl or aryl is provided. The process comprises degrading a compound of formula (II), (IIa), (IIb) or (IIc):                    
     wherein R 3  and R 10  are as defined above; Y is a cation; depending on the nature of Y, r is 1 or 2; and L is a suitable leaving group, to form a diazo compound. The diazo compound is reacted with a suitable transition metal catalyst, and the product thereof reacted with a sulphide of formula SR 6 R 7 , wherein R 6  and R 7  are independently alkyl, aryl or heteroaromatic, or R 6  and R 7  join together to form an optionally substituted ring which optionally includes an additional heteroatom. This product is then reacted with an aldehyde, ketone, imine or alkene.

The present invention relates to a process for the preparation ofoxiranes from aldehydes or ketones, of aziridines from imines, or ofcyclopropanes from alkenes.

It is known from WO95/11230 to prepare oxiranes, aziridines andcyclopropanes by reacting a diazo compound with an aldehyde, ketone,imine or alkene as appropriate in the presence of both a sulphide andeither an organometallic or an inorganic reagent to form a sulphurylide. As diazo compounds are difficult to handle due to their toxicityand explosive nature it would be advantageous to generate the diazocompounds in situ for this process thereby minimising the handling ofthese hazardous materials.

Thus, according to one aspect of the present invention there is provideda process for the preparation of an oxirane, aziridine or cyclopropaneof formula (I), wherein X is oxygen, NR⁴ or CHR⁵; R¹ is hydrogen, alkyl,aryl, heteroaromatic, heterocyclic or cycloalkyl; R² is hydrogen, alkyl,aryl, heteroaromatic, CO₂R⁸, CHR¹⁴NHR¹³, heterocyclic or cycloalkyl; orR¹ and R² join together to form a cycloalkyl ring; R³ and R¹⁰ are,independently, hydrogen, alkyl, aryl, heteroaromatic, CO₂R⁸, R⁸ ₃Sn,CONR⁸R⁹, trialkylsilyl or triarylsilyl; R⁴ is an electron withdrawinggroup; R⁵ is alkyl, cycloalkyl, aryl, heteroaromatic, SO₂R⁸, SO₃R⁸,COR⁸, CO₂R⁸, CONR⁸R⁹, PO(R⁸)₂, PO(OR⁸)₂ or CN; R⁸ and R⁹ areindependently alkyl or aryl; and R¹³ and R¹⁴ are independently hydrogen,alkyl or aryl; the process comprising the steps of:

(a) degrading a compound of formula (II), (IIa), (IIb) or (IIc), whereinR³ and R¹⁰ are as defined above; Y is a cation; depending on the natureof Y, r is 1 or 2; and L is a suitable leaving group, to form a diazocompound of formula (III) wherein R³ and R¹⁰ are as defined above;

(b) reacting the compound of formula (III) with a suitable transitionmetal catalyst

(c) reacting the product of step (b) with a sulphide of formula SR⁶R⁷,wherein R⁶ and R⁷ are independently alkyl, aryl or heteroaromatic, or R⁶and R⁷ join together to form an optionally substituted ring whichoptionally includes an additional heteroatom; and

(d) reacting the product of step (c) with a compound of formula (IV)wherein R¹ and R² are as defined above.

When the compound of formula (IV) is an alkene (that is, when X in thecompound of formula (IV) is CHR⁵) it is an electron deficient alkene.

When the process of the present invention is used to prepare an oxirane(that is, a compound of formula (I) wherein X is O, it is necessary tobalance the reactivity of the compound of formula (IV) against thereactivity of the product of step (c).

It is preferred that the compounds of formula (II) are degradedthermally (see, for example, Synth. Comm. 1978, 8(8) 569 or Bull. Soc.Chim. Belg. 1977, 86, 739); that the compounds of formula (IIa) aredegraded by contacting the compounds with, for example, leadtetraacetate or manganese dioxide (see, for example, the procedure ofHolton in J. Org. Chem. 1995, 60, 4725 and references cited therein);that the compounds of formula (IIb) are degraded thermally or by theaction of light (hv) (see, for example, the procedure of Doyle in Tett.Lett. 1989, 30, 3049 and references cited therein); and that thecompounds of formula (IIc) are degraded by thermal oxidation (see, forexample, the procedure of Horner in Chem. Ber. 1961, 94, 279).

The process of the present invention can be carried out in the presenceof a solvent. Suitable solvents include nitrites (such as acetonitrile),chlorinated solvents (such as CH₂Cl₂ or CHCl₃), aromatic solvents (suchas benzene, toluene and o-, m- or p-xylene), aliphatic alcohols (such asmethanol, ethanol or tert-butanol), chain or cyclic ethers (such asdiethyl ether, tert-butyl methyl ether, diisopropyl ether, glymes (forexample monoglyme, diglyme or triglyme) or tetrahydrofuran), aliphaticor alicyclic hydrocarbons (such as n-hexane or cyclohexane),N,N-dimethylformamide, sulpholane, dimethylsulphoxide orN-methylpyrrolidone.

Alternatively, the process can be carried out in a mixture of misciblesolvents (such as a mixture of water and acetonitrile), or differentreagents may be added in different solvents.

Phase transfer reagents can be used during the process of the presentinvention (for example when the process of the invention is carried outin a solvent and the reaction mixture is not homogenous). Suitable phasetransfer reagents include ammonium salts (such as benzyltriethylammoniumchloride) or crown ethers.

It is preferred that the process of the present invention is carried outat a temperature in the range −30 to 100° C., especially in the range 20to 70° C., such as at about 50° C.

In preferred embodiments of the first aspect of the present invention,the compound of formula (II), (IIa), (IIb) or (IIc) is decomposed in thepresence of the transition metal catalyst, the sulphide and thesubstrate compound of formula (IV).

According to a second aspect of the present invention, there is provideda process for the generation of diazo compounds, wherein a compound offormula II is thermally decomposed in the presence of an aprotic solventand a phase transfer catalyst, but in the absence of free base.

In the process of the second aspect of the present invention, theaprotic solvent may comprise a nitrile (such as acetonitrile); achlorinated solvent (such as CH₂Cl₂ or CHCl₃); an aromatic solvent (suchas benzene, toluene and o-, m- or p-xylene); a chain or cyclic ether(such as diethyl ether, tert-butyl methyl ether, diisopropyl ether, aglyme (for example monoglyme, diglyme or triglyme) or tetrahydrofuran);an aliphatic or alicyclic hydrocarbon (such as n-hexane or cyclohexane);N,N-dimethylformamide; sulpholane; dimethylsulphoxide orN-methylpyrrolidone. Acetonitrile is particularly preferred. Mostpreferably, the process according to the second aspect is carried outunder anhydrous conditions, ie in the substantial absence of water.Preferred phase transfer catalysts include quaternary ammonium salts,particularly trialkylbenzyl and tetraalkyl ammonium halides, especiallychlorides, and most preferably those wherein each alkyl is independentlya C₁₋₁₆ alkyl group. When the compound of formula II is a quaternaryammonium salt, the compound of formula II also serves as phase transfercatalyst. Most advantageously, the compound of formula II issubstantially insoluble in the aprotic solvent, and is employed as asuspension. It is particularly preferred that the compound of formula IIis a sodium salt. The thermal decomposition is often effected at atemperature of from 0 to 70° C., preferably from about 15 to about 50°C.

The compounds of formula (I) may have one, two or three chiralring-carbon atoms and the process of the first aspect of the presentinvention is capable of forming all structural isomers of the compoundsof formula (I). When one or more of R¹, R², R³, R⁴ or R⁵ is chiral itcan affect the stereochemical nature of the compound of formula (I)produced by the process of the present invention.

The term alkyl whenever it is used refers to straight or branched alkylchains preferably containing from 1 to 10, especially from 1 to 6, forexample from 1 to 4, carbon atoms. Alkyl is, for example, methyl, ethyl,n-propyl, n-butyl or tert-butyl. All alkyl groups are optionallysubstituted. Preferred substituents are one or more of aryl (such asphenyl), aryloxy (such as phenoxy), heteroaromatic, heterocyclic (suchas reduced forms of oxazole), cycloalkyl (such as cyclopropyl), C₁₋₆alkoxy (such as methoxy or ethoxy), C₁₋₆ thioalkyl (such as methylthio),halogen (to form, for example, CCl₃, CF₃ or CH₂CF₃), C₁₋₆ haloalkoxy(such as OCF₃), cyano, hydroxy or CO₂(C₁₋₆)alkyl. In addition the alkylgroups of R⁵ may terminate with an aldehyde (C(H)═O) group or beinterrupted with a carbonyl (C═O) group.

Halogen is fluorine, chlorine, bromine or iodine.

Alkoxy and haloalkoxy groups are straight or branched chains, preferablycontaining from 1 to 4 carbon atoms.

Haloalkoxy and haloalkyl groups do not have a halogen that issusceptible to nucleophilic substitution. Thus, a carbon atom of ahaloalkyl or haloalkoxy group must not carry a halogen atom and ahydrogen atom.

Cycloalkyl rings contain, preferably from 3 to 7, especially from 3 to 6carbon atoms. Cycloalkyl rings, can be substituted by one or more alkylgroups, CO₂R⁸ (wherein R⁸ is as defined above) or two ring carbons maybe joined to each other by a carbon chain containing from 1 to 4(preferably 1 or 2) carbon atoms to form a bicyclic structure.

Aryl includes naphthyl but is preferably phenyl.

Heteroaromatic includes 5- and 6-membered aromatic rings containing one,two, three or four heteroatoms selected from the list comprising oxygen,sulphur and nitrogen and can be fused to benzenoid ring systems.Examples of heteroaromatic rings are pyridyl, pyrimidyl, pyridazinyl,pyrazinyl, triazinyl (1,2,3-, 1,2,4- and 1,3,5-), furyl, thienyl,pyrrolyl, pyrazolyl, imidazolyl, triazolyl (1,2,3- and 1,2,4-),tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl,isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, indolinyl,isoindolinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazole,benzthiazole, oxadiazole and thiadiazole.

All aryl and heteroaromatic groups are optionally substituted. Preferredsubstituents include one or more of alkyl, haloalkyl, C₁₋₆ alkoxy,halogen, C₁₋₆ haloalkoxy, cycloalkyl, nitro, cyano or CO₂(C₁₋₆)alkyl.

Heterocyclic is used in relation to non-aromatic rings and includesinclude 5- and 6-membered rings containing one, two or three heteroatomsselected from the group comprising oxygen, sulphur and nitrogen.Examples are piperidine, pyrrolidine, azetidine, morpholine,tetrahydrofuran, tetrahydrothiophene, pyrroline, piperazine,isoxazoline, oxazoline and reduced forms of heteroaromatics notpreviously mentioned. Heterocyclic rings are optionally substituted andpreferred substituents include one or more alkyl groups.

When the compound of formula (IV) is an aldheyde, R² is preferably anoptionally substituted alkyl group comprising from 1 to 10 carbon atoms;an optionally substituted phenyl group, particularly substituted at oneor both of the positions ortho or para to the aldehyde moiety or anoptionally substituted heteroaromatic group comprising a 5 or 6 memberedring, especially comprising 1,2 or 3 nitrogen heteroatoms.

When the compound of formula (IV) is a ketone, at least one of R¹ and R²often represents an optionally substituted alkyl group comprising from 1to 10 carbon atoms, or forms a cycloalkyl group, and most often thecarbon alpha to the keto group carries one, and preferably two hydrogenatoms. When one or both, preferably one, of R¹ and R² represents an arylor heteroaromatic group, the ring positions adjacent to the keto grouppreferably carry hydrogen atoms. Aliphatic ketones, particularly thosecomprising up to 16 carbon atoms are most preferred.

When the compound of formula (IV) is an alkene, it is preferred that thealkene is conjugated with an electron withdrawing group, preferably acarbonyl, nitro, cyano phosphoryl or sulphonyl group, especially a groupof formula SO₂R⁸, SO₃R⁸, COR⁸, CO₂R⁸, CONR⁸R⁹, CN, P(O)(R⁸)₂, especiallyP(O)(aryl)₂ or PO(OR⁸)₂; wherein R⁸ and R⁹ are as defined above. When R⁸or R⁹ comprises an alkyl group, it is preferably a C₁₋₆ alkyl group,which may be substituted. When R⁸ or R⁹ comprises an aryl group, it ispreferably a phenyl group, which may be substituted.

When the compound of formula (IV) is an imine, it is preferred that oneof R¹ and R² represents H, alkyl, phenyl or a heteroaromatic group, theother representing alkyl, aryl or a heteroaromatic group, wherein anyalkyl group preferably comprises from 1 to 10 carbon atoms; and isoptionally substituted; any phenyl group is optionally substituted,particularly at one or both of the positions ortho or para to thealdehyde moiety and any heteroaromatic group comprises a 5 or 6 memberedring, especially comprising 1,2 or 3 nitrogen heteroatoms, and isoptionally substituted. R⁴ is an electron withdrawing group, such as agroup of formula SO₂R⁸, SO₃R⁸, COR⁸, CO₂R⁸, CONR⁸R⁹, CN, P(O)(R⁸)₂,especially P(O)(aryl)₂ or PO(OR⁸)₂; wherein R⁸ and R⁹ are as definedabove. When R⁸ or R⁹ comprises an alkyl group, it is preferably a C₁₋₆alkyl group, which may be substituted. When R⁸ or R⁹ comprises an arylgroup, it is preferably a phenyl group, which may be substituted.

In the sulphides which are employed in the process of the first aspectof the present invention, it is preferred that at least one of R⁶ and R⁷represents an alkyl group. In many embodiments, the sulphide is analiphatic sulphide.

Examples of sulphides that can be employed include those compoundslisted as structures (A) to (AB) below.

The ring formed when R⁶ and R⁷ join preferably contains from 1 to 12(for example from 2 to 10, especially from 2 to 6 [see, for example,(B), (C) or (C′)]) carbon atoms, optionally includes an additionalheteroatom (preferably a nitrogen, oxygen or sulphur atom) [see, forexample, (D) or (J)] and is optionally substituted. This ring may befused to other rings (for example aryl [such as naphthyl, see, forexample, (A)] or mono- or bi-cyclic carbon ring systems (such ascyclohexane [see, for example, (F), (G), (K) or (L)] or camphor [see,for example, (D) or (J)]) which are optionally substituted (for examplesubstituted with alkyl, aryl or heteroaryl). When the cyclic sulphide isa 1,3-oxathiane, the 2-position is preferably unsubstituted or carriesone substituent wherein the carbon alpha to the 2-position carries atleast one, and preferably at least two hydrogen atoms, and particularlysuch substituents are primary or secondary alkyl groups. The ring mayalso incorporate carbon-carbon double bonds, and when such a double bondis present, there is preferably only one such bond in the ring alsocomprising the S atom. Cyclic sulphides may also be substituted by analkenyl group, and, when present, such an alkenyl substituentparticularly substitutes a ring fused to the ring comprising the sulphuratom.

A particular class of cyclic sulphides which can be employed in theprocess of the present invention has the general chemical formula (VI):

wherein Z represents —CH₂—, O, S, —CHalkyl-, C(alkyl)₂— or NR⁴, each ofR^(d−k) independently represents H, alkyl or alkoxyalkyl or are linkedto form a cyclic moiety, provided that at least 2 of R^(d), R^(e), R^(j)and R^(k) represent H, and R⁴ is as hereinbefore defined.Advantageously, the nature of R^(d−k) is selected such that the sulphideis chiral.

In certain embodiments, two of R^(d−k) can be linked so as to form abridging group, for example comprising 1 to 4 bridging atoms, or a fusedcyclic group, for example forming a 5 or preferably 6, membered ring. Incertain preferred embodiments, either R^(d) and R^(e) or R^(j) and R^(k)are linked to form a cyclic group, preferably forming a 5-, orespecially a 6-membered ring.

The compounds of formula (VI) where either R^(d) and R^(e) or R^(j) andR^(k) are linked to form a cyclic group are novel and form an aspect ofthe present invention.

The compounds of formula (VI) wherein Z represents O, and the nature ofthe groups R^(d−k) are such that the compounds are chiral are novel andform an aspect of the present invention. In certain preferred compoundsof formula (VI), one of R^(d) and R^(e) and one of R^(f) and R^(g), orone of R^(h) and R^(i) and one of R^(j) and R^(k) are linked to form asix membered ring. In other preferred compounds of formula (VI), both ofR^(f) and R^(g) and one of R^(d) and R^(e) are independently alkyl,especially C₁₋₆ Alkyl or alkoxyalkyl, especially C₁₋₄alkoxyC₁₋₆alkyl,with the remainder of R^(d−k) representing hydrogen.

A further class of sulphides which may be employed in the process of thepresent invention have the chemical formula (VII)

wherein R^(m) and R^(n) are each independently alkyl, especially C₁₋₆alkyl or alkoxyalkyl, especially C₁₋₄alkoxyC₁₋₆alkyl.

Alternatively, the sulphide of formula SR⁶R⁷ may be a bis-sulphide (suchas (E)) or may be incorporated into the molecular structure of theorganometallic compound (such as (H)).

The substituents referred to in structures (A)-(AB) are defined asfollows: R′, R″ and R′″ are, independently, hydrogen, alkyl,alkoxyalkyl, aryl or heteroaryl, and are particularly hydrogen, C₁₋₆alkyl or C₁₋₄alkoxyC₁₋₆alkyl; in (F), (G), (L) and (O) R′ and R″ mayjoin to form a 3 to 8-membered carbocyclic ring optionally substitutedwith alkyl; in (D), R^(a) is hydrogen or primary or secondaryunsubstituted, mono- or di-substituted alkyl, and R^(b) is hydrogen,alkyl, aryl or heteroaryl; R^(a) may also beCH₂O(CH₂)_(n)O(CH₂)_(m)OR^(b) or (CH₂)_(p)CO(CH₂)COR^(b); oralternatively R^(a) is linked to a polymer support; wherein n, m and pare integers (preferably 1-10); in (E), R^(c) is (Q) or (CH₂)_(q)Sr′;R²² is hydrogen, alkyl or trialkylsilyl; and R²³ is hydrogen or alkyl;wherein q is an integer of 2 or more (preferably 2-10). It is preferredthat R^(b) is hydrogen.

The groups R^(a) and R^(b) in structure (D) are, for example:

R^(a) R^(b) CH₃ H (CH₃)₂CH H CH₂OCH₃ H CH₂O(CH₂)₃CH₃ H CH₃(CH₂)₃ HCH₂OC₆H₅ H CH₃ CH₃ CH₃(CH₂)₂ CH₃(CH₂)₂ CH₂OH H CH₂O(CO)CH₃ HCH₂O(CO)(4-NO₂—C₆H₄) H CH₂CN H

In structures (P), (R), (S), (T), (U), (V), (W), (X), (Y), (Z), (AA) and(AB), the methyl and iso-propyl groups, particularly those methyl groupssubstituting the ring comprising the S atom, may be replaced by analternative alkyl group, preferably a C₁₋₆ alkyl group, most preferablya C₁₋₄ alkyl group, or by an alkoxyalkyl group, preferably aC₁₋₄alkoxyC₁₋₆alkyl group, most preferably a C₁₋₄ alkoxymethyl group.

Suitable transition metal catalysts are those which convert diazocompounds to carbenes, and include particularly rhodium, ruthenium,copper, nickel and palladium compounds, and especially complexes. Whenthe transition metal catalyst comprises a rhodium compound, it iscommonly a rhodium (0) or rhodium (II) compound, and preferably rhodium(II). When the transition metal catalyst comprises a ruthenium compound,it is commonly a ruthenium (0), (II) or (III) compound, and preferably aruthenium (II) compound. When the transition metal catalyst comprises acopper compound, it is commonly a copper (0), (I) or (II) compound,including metallic Cu, and preferably a Cu(I) or (II) compound. When thetransition metal catalyst comprises a nickel compound, it is commonly anickel (0) or (II) compound, and preferably a nickel (II) compound. Whenthe transition metal catalyst comprises a palladium compound, it iscommonly a palladium (0) or palladium (II) compound, and preferably apalladium (II) compound.

Suitable transition metal catalysts preferably comprise rhodium orruthenium. Suitable reagents include Rh₂(OCOR.)₄ or Ru₂(OCOR.)₄ [whereinR. is hydrogen, alkyl (preferably methyl), C₁₋₄ perfluoroalkyl (such astrifluoromethyl, 2,2,2-trifluoroethyl or pentafluoroethyl), aryl,(CHOH)alkyl or (CHOH)aryl], such as Rh₂(OCOCH₃)₄ or Rh₂(OCOCF₃)₄; or canbe RuCl₂(P(C₆H₅)₃)₂, RuCl(H₂C₂B₉H₁₀)(P(C₆H₅)₃)₂ or RH₆(CO)₁₆.

Alternatively, suitable transition metals comprise copper, nickel orpalladium. Examples of suitable reagents include CuBr, CuCl, CuOSO₂CF₃,CuBr₂, CuCl₂, CuSO₄, Cu(CH₃CO₂)₂ a copper compound of formula (V)(wherein R²⁰ and R²¹ are both methyl [that is, Cu(acetylacetonate)₂],phenyl or tert-butyl, or R²⁰ is phenyl and R²¹ is methyl),[Cu(CH₃CN)₄]BF₄, NiBr₂, NiCl₂, NiSO₄, Cu(CH₃CO₂)₂, the nickel analogueof the compound of formula (V) (wherein R²⁰ and R²¹ are both methyl[that is, Ni(acetylacetonate)₂], phenyl or tert-butyl, or R²⁰ is phenyland R²¹ is methyl), Pd(OCOCH₃)₂, Pd(acetylacetonate)₂, Pd(CH₃CN)₂Cl₂ orPd(C₆H₅CN)₂Cl₂.

Suitable cations (Y) for compounds of formula (II) are cations of alkalimetals (especially sodium, potassium or lithium), cations of alkalineearth metals (such as magnesium or calcium) or quaternary ammonium salts[such as (C₁₋₆ alkyl)₄N⁺, wherein the alkyl group is unsubstituted, forexample (CH₃(CH₂)₃)₄N⁺]. It is preferred that Y is the cation of sodium(that is, Na⁺).

Suitable leaving groups (L) for compounds of formula (II) includearylsulphonyl (that is arylSO₂) compounds (wherein the aryl is mono-,di- or tri-substituted with unsubstituted C₁₋₁₀ alkyl or ismonosubstituted with nitro) or unsubstituted C₁₋₁₀ alkylsulphonylcompounds. Examples of suitable leaving groups are p-tosyl,2,4,6-tri-iso-propylphenylsulphonyl, 2-nitrophenylsulphonyl and mesyl.

The compounds of formula (II) can be prepared by adaptation of methodsfound in the literature. For example, the compounds wherein L is tosylcan be prepared from tosyl hydrazones by adapting the methods of Creary(Organic Synth. 1986, 64, 207), Bertz (J. Org. Chem. 1983, 48, 116) orFarnum (J. Org. Chem. 1963, 28, 870). Tosyl hydrazones can be preparedfrom tosyl hydrazides which can in turn be prepared by reacting tosylhydrazine with an aldehyde of formula R³CHO.

In many embodiments, only one, or neither, of R³ and R¹⁰ representshydrogen. Preferably one of R³ or R¹⁰ is an alkyl, aryl or amide group.When one of R³ or R¹⁰ represents a group of formula —CONR⁸R⁹, especiallywhen X is O, it is preferred that the sulphide employed is not a1,3-oxathiane.

It is preferred that the nucleophilicity of the sulphide of formulaSR⁶R⁷ is such that the rate of reaction of the product of step (b) withthe sulphide of formula SR⁶R⁷ is greater than the rate of reaction ofthe product of step (b) with the compound of formula (III).

It is possible to influence the stereochemistry of the compound offormula (I) produced by the process. This can be done by using a chiralsulphide of formula SR⁶R⁷ (such as structures (C′), (D), (F), (G), (H),(J), (K) or (L), (M), (N), (O), (O″), (P), and (R) to (AB)). Therelative amounts of the stereochemical products will depend on thenature of the chiral sulphide used. Thus, in a further aspect thepresent invention provides a process as hereinbefore described wherein achiral sulphide is used.

In another aspect the present invention provides a process as previouslydescribed wherein the organometallic reagent is present in a less thanstoichiometric amount (such as from 0.5 to 0.001, for example from 0.015to 0.005, equivalents).

In a further aspect the present invention provides a process aspreviously described wherein a less than a stoichiometric amount ofsulphide is used in relation to the amount of compound of formula (IV).For example it is preferred that the amount of sulphide used is in therange 1.00-0.01 equivalents (such as in the range 0.75-0.02 (for example0.5-0.05 (particularly about 0.2)) equivalents).

In a further aspect the present invention provides a process ashereinbefore described wherein a chiral sulphide is used in an amount inthe range of 0.5-0.1 equivalents relative to the amount of compound offormula (IV) used.

In a still further aspect the present invention provides a process ashereinbefore described wherein the compound of formula (IV) is analdehyde, ketone, imine or alkene.

In another aspect the present invention provides a process as definedabove wherein X is oxygen.

In a further aspect the present invention provides a process forpreparing a compound of formula (I) wherein X is oxygen and R¹ ishydrogen, and the process is conducted under the following conditions:

Compound of formula 1 equivalent (IV) wherein R¹ is hydrogen RhodiumAcetate 1 mol % Compound of formula 1.5 equivalents (II) Benzyltriethyl-20 mol % ammonium Chloride Tetrahydrothiophene 20 mol % Acetonitrile 3cm³/mmol compound of formula (IV) wherein R¹ is hydrogen Temp/Time40-45° C./3-5 hours

In a still further aspect the present invention provides a process forpreparing a compound of formula (I) wherein X is oxygen, wherein: acompound of formula (II) (wherein Y is Na⁺) is used in step (a) and thiscompound is degraded in situ at low temperature for extended reactiontimes (typically 30° C. for 32 hours) and acetonitrile is used assolvent. In another aspect the sulphide of formula R⁶R⁷ is used in 100mol %.

In a further aspect the present invention provides a process ashereinbefore described wherein a compound of formula (II) is used instep (a). In another aspect the present invention provides a process ashereinbefore described wherein and using a compound of formula (II) instep (a) wherein the compound of formula (II) is prepared from thecorresponding hydrazone (that having been prepared by contacting thecorresponding aldehyde or ketone with a suitable hydrazide).

In a still further aspect the present invention provides a process forthe preparation of a compound of formula (I), the process comprising:

1. adding a compound of formula (II) to a mixture of:

a compound of formula (IV),

a sulphide of formula SR⁶R⁷ and

either a rhodium compound of formula Rh₂(OCOR.)₄ (wherein R. ispreferably methyl) or a copper (II) acetoacetonate,

a solvent (preferably acetonitrile or a mixture of acetonitrile andwater) and, optionally,

a phase transfer catalyst (preferably benzyltriethylammonium chloride);

2. heating the resulting mixture to a temperature in the range 20-60° C.for a time period (preferably 1-48 hours); and

3. extracting the compound of formula (I) from the mixture so formed.

The following Examples illustrate the invention. The followingabbreviations are used throughout the Examples:

m = multiplet s = singlet d = doublet dt = doublet of triplets brs =broad singlet dd = doublet of doublets brd = broad doublet EtOAc = ethylacetate tosyl = p-toluenesulphonyl

All solvents used in reactions were distilled prior to use.Tetrahydrofuran (THF) and diethyl ether were freshly distilled fromsodium under an atmosphere of dry nitrogen using benzophenone as anindicator. Acetonitrile and dichloromethane (DCM) were freshly distilledfrom calcium hydride. Reagents were either used as received fromcommercial sources or purified by recognised methods. Petroleum ether(petrol) refers to that fraction which boils in the range 40-65° C.Liquid aldehydes were distilled prior to use, either neat or fromcalcium sulphate. Copper (II) acetylacetonate was sublimed prior to use.

All reactions, unless otherwise stated, were carried out in oven driedglassware under an atmosphere of dry nitrogen or argon.

Flash chromatography was performed using Kieselgel 60 F254 and on C560,40-63 micron silica gel. All reactions were monitored by thin layerchromatography (TLC) carried out on aluminium sheets precoated with60F₂₅₄ silica gel, unless otherwise stated, and were visualised by UVlight at 254 nm, then potassium permanganate solution, phosphomolybdicacid (PMA) solution or anisaldehyde solution (epoxides appeared to stainvery intensely with PMA solution).

¹H-NMR were recorded on a Bruker ACF-250 spectrometer operating at250.13 MHz or a Bruker WH400 instrument operating at 399.7 MHz. Theobserved spectra were for solutions in deuterochloroform unlessotherwise stated. The chemical shifts (d) were recorded in parts permillion (ppm) relative to tetramethylsilane as an internal standard; allcoupling constants, J, are reported in Hz.

¹³C-NMR spectra were recorded on a Bruker ACF-250 spectrometer operatingat 62.9 MHz. The spectra were recorded for solutions indeuterochloroform unless otherwise stated. The chemical shift (d) wererecorded relative to deuteriochloroform (or relative solvent peak) asinternal standard in a broad band decoupled mode; the multiplicitieswere obtained by using 135° and 90° “Distortionless Enhancement byPolarisation Transfer” (DEPT) or Off Resonance Decoupling experiments toaid in assignments (q, methyl; t, methylene; d, methine; s, quaternary).

Infra red spectra were recorded on a Perkin-Elmer 157G FT-IR, either asliquid films between sodium chloride plates or as KBr discs.

Mass spectra were recorded on a Kratos MS 25 or MS 80 instrument with aDS 55 data system using either an ionising potential of 70 eV (EI), orby chemical ionisation (iso-butane) (CI) or fast atom bombardment (FAB)in 3NBA matrix.

Melting points (m.p.) were recorded on a Kofler Hot Stage Micro MeltingPoint Apparatus and are uncorrected.

Optical rotations were recorded on a Perkin-Elmer 141 Polarimeter atambient temperature. [a] values are reported as 10⁻¹ deg cm² g⁻¹.Microanalysis was carried out on a Perkin-Elmer 2400 Elemental Analyser.

High pressure liquid chromatography (HPLC) analysis, used to determineenantiomeric excesses, was carried out using a Gilson 303 HPLC pump,Waters 994 Tuneable Absorbance Detector or a Waters 2200 Data Module(analysis conditions are given below).

Diastereomeric ratios were determined by NMR analysis.

PREPARATION OF ARYL TOSYL HYDRAZONES

Aryl tosyl hydrazones were prepared according to the method of Creary(Organic Synth. 1986, 64, 207).

To a rapidly stirred suspension of p-toluenesulphonyl hydrazide (5.0 g,26.8 mmol) in methanol (10 cm³) was added an aldehyde (24 mmol) dropwise(solid aldehydes were added as a methanol solution or portionwise). Amildly exothermic reaction ensued and the hydrazide dissolved. Within5-10 minutes the tosyl hydrazone began to precipitate. Afterapproximately 30 minutes the mixture was cooled to 0° C. and the productremoved by filtration, washed with a small quantity of methanol and thenrecrystallised from hot methanol.

Benzaldehyde tosyl hydrazone: Isolated as white needles (5.40 g, 82%),m.p. 127-128° C.; dH 2.37 (3H,s), 7.26-7.37 (5H,m), 7.52-7.61 (2H,m),7.80 (1H,s), 7.89 (2H,d, J 9), 8.44 (1H, brs).

4-Methylbenzaldehyde tosyl hydrazone: Isolated as white needles (6.22 g,90%), m.p. 144-146° C.; (found C, 62.48; H, 5.52; N, 9.85. C₁₅H₁₆N₂SO₂requires C, 62.5; H, 5.5; N, 9.7%); u_(max) (KBr disc)/cm⁻¹ 3215, 1165,1049, 814; d_(H) 2.32 (3H,s), 2.37 (3H,s), 7.14 (2H,d, J 8), 7.31 (2H,d,J 8), 7.45 (2H,d, J 8), 7.75 (1H,s), 7.88 (2H, d, J 8.2), 8.19 (1H,brs);d_(C) 21.5 (q), 21.6 (q), 127.4 (d), 127.9 (d), 129.4 (d), 129.7 (d),130.5 (s), 135.3 (s), 140.8 (s), 144.2 (s), 148.3 (d); m/z (EI) 288 (M⁺,63%), 133 (63), 104 (100), 91 (41), 77 (25).

4-Chlorobenzaldehyde tosyl hydrazone: Isolated as colourless needles(6.74 g, 91%), m.p. 146-148° C.; (Found C, 54.27; H, 4.14; N, 9.21.C₁₄H₁₃N₂SO₂Cl requires C, 54.5; H, 4.4; N, 9.1%); u_(max) (KBrdisc)/cm⁻¹ 3187, 1332, 1332, 1169; d_(H) 2.41 (3H,s), 7.30-7.35 (4H,m),7.49 (2H,d, J 7.8), 7.75 (1H,s), 7.87 (2H,d, J 7.8), 8.42 (1H,brs);d_(C) 21.6 (q), 127.9 (d), 128.4 (d), 128.9 (d), 129.8 (d), 131.7 (s),135.1 (s), 136.3 (s), 144.5 (s), 146.5 (d); m/z (EI) 308 (M⁺, 49%), 152(38), 124 (100), 89, (100), 63 (32).

3-Nitrobenzaldehyde tosyl hydrazone: Isolated as pale yellow needles(5.59 g, 73%), m.p. 154-156° C.; (Found C, 52.72; H, 3.99; N, 13.21.C₁₄H₁₃N₃O₄S requires C, 52.7; H, 4.1; N,13.2%); u_(max) (KBr disc)/cm⁻¹3218, 1533, 1349, 1166, 819; d_(H) 2.43 (3H,s), 7.35 (2H,d, J 9), 7.55(1H,dd, J 9, 6), 7.85-7.97 (4H,m), 8.18 (1H,dd, J 9, 5.8), 8.35 (1H,s),8.54 (1H,brs); d_(C) 21.7 (q), 122.0 (d), 124.7 (d), 128.0 (d), 129.8(d), 129.9 (d), 132.6 (d), 134.9 (s), 135.0 (s), 144.4 (d), 144.8 (s),148.5 (s); m/z (EI) 319 (M⁺, 54%), 314 (30), 280 (85), 216 (78), 188(50), 141 (48), 111 (42), 91 (38), 77 (100).

4-Methoxybenzaldehyde tosyl hydrazone: Isolated as white crystals, (6.10g, 83%), m.p. 103-105° C.; (Found C, 59.24; H, 5.16; N, 9.17.C₁₅H₁₆N₂O₃S requires C, 59.2; H, 5.3; N, 9.2%); u_(max) (KBr disc)/cm⁻¹3222, 1161, 1044; d_(H) 2.35 (3H,s), 3.75 (3H,s), 6.81 (2H,d, J 10.8),7.25 (2H,d, J 8.1), 7.48 (2H,d, J 10.8), 7.74 (1H,s), 7.88 (2H,d, J8.2), 8.55 (1H,brs); d_(C) 21.6 (q), 55.4 (q), 114.1 (d), 126.0 (s),127.9 (d), 128.9 (d), 129.7 (d), 135.3 (s), 144.2 (s), 148.4 (d), 161.4(s); m/z (EI) 304 (M⁺, 57%), 149 (94), 139 (43), 135 (60), 121 (100), 91(90), 77 (48).

4-Cyanobenzaldehyde tosyl hydrazone: Isolated as pale yellow crystals(5.95 g, 83%), m.p. 161-164° C.; (Found C, 60.22; H, 4.34; N, 14.06.C₁₅H₁₃N₃O₂S requires C, 60.2; H, 4.3; N, 14.0%); u_(max) (KBr disc)/cm⁻¹3170, 2230, 1171; d_(H) 2.40 (3H,s), 7.32 (2H,d, J 8), 7.64 (4H,m), 7.80(1H,s), 7.88 (2H,d, J 8), 8.87 (1H,brs); d_(C) 21.7 (q), 113.4 (s),118.4 (s), 127.6 (d), 127.9 (d), 129.9 (d), 132.4 (d), 134.9 (s), 137.4(s), 144.8 (s), 144.9 (d); m/z (EI) 299 (M⁺, 6%), 156 (27), 143 (28),115 (100), 91 (57), 65 (36).

2,4,6-Trimethylbenzaldehyde tosyl hydrazone: Isolated as white needles(5.69 g, 75%), m.p. 159-161° C.; (Found C, 64.47; H, 6.38; N, 8.89; S,10.06. C₁₇H₂₀N₂O₂S requires C, 64.5; H, 6.3; N, 8.9; S, 10.1%); u_(max)(KBr disc)/cm³¹ ¹ 3203, 1608, 1557, 1326, 1165; d_(H) 1.95 (3H,s), 2.25(6H,m), 2.41 (3H,m), 6.84 (2H,m), 7.25-7.35 (2H,m), 7.55 (1H,brd), 7.80(2H,m); d_(C) 21.1 (q), 21.3(q), 21.6(q), 127.1 (s), 128.1 (d),129.6(d), 135.3(s), 137.9 (s), 139.3 (s), 144.2 (s), 148.0 (d); m/z (EI)316 (M⁺, 37%), 161 (100), 132 (96), 91 (77).

Preparation of Alkyl Tosyl Hydrazones

Tosyl hydrazones of aliphatic aldehydes were prepared according to themethod of Bertz (J. Org. Chem. 1983, 48, 116).

Pivaldehyde Tosyl Hydrazone

p-Toluenesulphonyl hydrazide (3.24 g, 17.4 mmol) was added to 35 cm³ ofTHF. The mixture was stirred vigorously and then filtered to removeinsoluble material (ca. 100 mg). To the resulting solution was addedpivaldehyde (1.92 cm³, 17.4 mmol) dropwise. The mixture was then stirredmagnetically for 1 hour after which time TLC indicated the reaction wascomplete. The THF was then removed under reduced pressure to give awhite solid which was purified by recrystallisation from diethyl ether.The product was isolated as a white solid (2.31 g). Concentration of thefiltrate gave a second crop (0.52 g, total yield 64%); m.p. 110-112° C.;u_(max) (KBr disc)/cm⁻¹ 3199, 1327, 1166; d_(H) 0.98 (9H,s), 2.42(3H,s), 7.07 (1H,s), 7.28 (2H,d, J 8), 7.80-7.82 (3H,m); d_(C) 21.6 (q),27.1 (q), 35.1 (s), 128.3 (d), 129.4 (d), 135.0 (s), 144.0 (s), 160.2(d); m/z (EI) 254 (M⁺, 8%), 157 (36), 139 (25), 91 (100), 65 (48), 55(97).

Preparation of Ketone-derived Tosyl Hydrazones

Aryl alkyl tosyl hydrazones were prepared by modification of the methodof Farnum (J. Org. Chem. 1963, 28, 870).

Acetophenone Tosyl Hydrazone

A suspension of p-toluenesulphonyl hydrazide (3.11 g, 16.7 mmol) inglacial acetic acid (4 cm³) was heated to 65° C. and stirred until allof the solid had dissolved. Acetophenone (1.94 cm³, 16.7 mmol) was thenadded in one portion and heating continued until precipitation of thehydrazone occurred (approximately 5 minutes). The mixture was thencooled and the product removed by filtration. The pale yellow solid waswashed with cold acetic acid, cold aqueous acetic acid then water. Itwas then air dried. The crude material was purified by recrystallisationfrom hot methanol. The hydrazone was obtained as a white solid (3.30 g,69%); m.p. 130-132° C. (decomp.); (Found C, 62.24; H, 5.47; N, 9.82.C₁₅H₁₆N₂O₂S requires C, 62.5; H, 5.6; N, 9.7%); u_(max) (KBr disc)/cm⁻¹3223, 1166, 1050, 919; d_(H) 2.19 (3H,s), 2.42 (3H,s), 7.28 (5H,m), 7.63(2H,m), 7.96 (2H,m), 8.07 (1H,brs); d_(C) 13.4 (q), 21.6 (q), 126.3 (d),127.9 (d), 128.1 (d), 128.3 (d), 129.6 (d), 135.4 (s), 137.3 (s), 144.1(s), 152.6 (s); m/z (EI) 288 (M⁺, 43%), 133 (100), 104 (85), 92 (63), 77(32), 65 (31).

Preparation of Tosyl Hydrazone Sodium Salts

Tosyl Hydrazone salts were prepared according to the method of Creary(Organic Synth. 1986, 64, 207).

A 1M sodium methoxide solution was prepared by adding sodium (288 mg,12.5 mmol) to anhydrous methanol (12.5 cm³) with external cooling. Onceall of the metal had dissolved a tosyl hydrazone (12.35 mmol) was addedand the mixture stirred until all of the solid had dissolved. (Thesodium salts of tosyl hydrazones derived from 4-methylbenzaldehyde and3-nitrobenzaldehyde precipitated from methanol and were filtered, washedand dried under vacuum.) After stirring for a further 15 minutes themethanol was removed under reduced pressure (at room temperature). Thelast traces of methanol were removed under high vacuum. The solidhydrazone salt was then ground to give a free flowing powder using amortar and pestle.

Tosyl hydrazone sodium salts are best stored in a cool place in theabsence of direct light.

Benzaldehyde tosyl hydrazone sodium salt: Isolated as a white solid,(Found C, 56.78; H, 4.34; N, 9.22. C₁₄H₁₃N₂SO₂Na requires C, 56.8; H,4.4; N, 9.5%); u_(max) (KBr disc)/cm⁻¹ 3056, 1245, 1129, 1088,1054,1037; d_(H) (D₂O) 2.26 (3H,s), 7.29 (5H,m), 7.49 (2H,d, J 10), 7.71(2H,d, J 10), 7.96 (1H,s); d_(C) (D₂O) 20.39 (q), 126.2 (d), 126.5 (d),128.5 (d), 129.2 (d), 135.6 (s), 139.2 (s), 142.3 (s), 145.5 (d); m/z(FAB) 297 (M⁺+1, 84%).

4-Methylbenzaldehyde tosyl hydrazone sodium salt: Isolated as a whitesolid, u_(max) (KBr disc)/cm⁻¹ 3518, 1236, 1137,1090, 1044, 662; d_(H)(D₂O) 2.23 (3H,s), 2.26 (3H,s), 7.11 (2H,d, J 8), 7.26 (2H,d, J 8), 7.37(2H,d, J 8), 7.70 (2H,d, J 8), 7.89 (1H,s); d_(C) (D₂O) 20.3 (q), 20.5(q), 126.4 (d), 126.5 (d), 129.2 (d), 129.3 (d), 132.7 (s), 139.2 (s),142.5 (s), 146.0 (d); m/z (FAB) 311 (M⁺+1, 41%), 308 (25), 307 (100);(Found [M+H]⁺ 311.0834. C₁₅H₁₆N₂O₂SNa requires m/z, 311.0830).

4-Chlorobenzaldehyde tosyl hydrazone sodium salt: Isolated as anoff-white solid, u_(max) (KBr disc)/cm⁻¹ 1239, 1129, 1087, 1062, 1030;d_(H) (D₂O) 2.10 (3H,s), 7.05-7.12 (4H,m), 7.28 (2H,d, J 8), 7.65 (2H,d,J 8), 7.80 (1H,s); d_(C) (D₂O) 20.4 (q), 126.5 (d), 127.5 (d), 128.3(d), 129.3 (d), 133.3 (s), 134.2 (s), 139.1 (s), 142.2 (s), 144.2 (d);m/z (FAB) 331 (M⁺+1, 80%); (Found [M+H]⁺ 331.0278. C₁₄H₁₂N₂O₂SClNarequires m/z, 331.0284).

3-Nitrobenzaldehyde tosyl hydrazone sodium salt: Isolated as a yellowsolid, (Found C, 49.14; H, 3.50; N, 12.0. C₁₄H₁₂N₃O₄SNa requires C,49.3; H, 3.5; N, 12.3%); u_(max) (KBr disc)/cm⁻¹ 1530, 1351, 1237, 1142,1127, 1084, 1041; d_(H) (D₂O) 2.14 (3H,s), 7.13-7.21 (3H,m), 7.55 (1H,d,J 7.5), 7.58-7.76 (3H,m), 7.77 (1H,s), 8.01 (1H,m; d_(C) (D₂O) 20.4 (q),120.1 (d), 122.2 (d), 126.6 (d), 129.2 (d), 132.2 (d), 137.3 (s), 139.0(s), 142.0 (d), 142.4 (s), 147.5 (s); m/z (FAB) 342 (M⁺+1, 22%), 201(56).

4-Methoxybenzaldehyde tosyl hydrazone sodium salt: Isolated as a whitesolid, u_(max) (KBr disc)/cm⁻¹ 1511, 1248, 1234, 1141, 1088, 1031; d_(H)(D₂O) 2.20 (3H,s), 3.66 (3H,s), 6.77 (2H,d, J 8), 7.20 (2H,d, J 8), 7.37(2H,d, J 8), 7.68 (2H,d, J 8.2), 7.86 (1H,s); d_(C) (D₂O) 20.4 (q), 55.2(q), 113.9 (d), 126.5 (d), 127.8 (d), 128.7 (s), 129.3 (d), 139.3 (s),142.4 (s), 145.6 (d), 159.1 (s); m/z (FAB) 327 (M⁺+1, 100%), 298 (40);(Found [M+H]⁺ 327.0779. C₁₅H₁₆N₂O₃SNa requires m/z, 327.0799).

4-Cyanobenzaldehyde tosyl hydrazone sodium salt: Isolated as a paleyellow solid, u_(max) (KBr disc)/cm⁻¹ 3064, 2225, 1238, 1133, 1087,1045; d_(H) (D₂O) 2.16 (3H,s), 7.18 (2H,d, J 8), 7.40 (4H,m), 7.67(2H,d, J 8), 7.81 (1H,s); d_(C) (D₂O) 20.5 (q), 119.5 (s), 126.4 (d),126.5 (d), 129.4 (d), 132.5 (d), 140.9 (s), 143.3 (d), 143.5 (s) (2 ipsoC's not observed); m/z (FAB) 322 (M⁺+1, 12%), 201 (100).

2,4,6-Trimethylbenzaldehyde tosyl hydrazone sodium salt: This compoundappeared to decompose slowly at room temperature and was thereforestored at +4° C. Isolated as a white solid, u_(max) (KBr disc)/cm⁻¹2965, 1247, 1232,1136, 1091; d_(H) (D₂O) 2.01 (6H,s), 2.14 (3H,s), 2.31(3H,s), 6.75 (2H,s), 7.26 (2H,d, J 8), 7.68 (2H,d, J 8), 8.05 (1H,s);d_(C) (D₂O) 19.5 (q), 20.0 (q), 20.5 (q), 126.9 (d), 128.4 (d), 129.3(d), 130.5 (s), 137.2 (s) 138.1 (s), 139.3 (s), 142.5 (s), 145.4 (d);m/z (FAB) 339 (M⁺+1, 100%); (Found [M+H]⁺ 339.1146. C₁₇H₂₀N₂O₂SNarequires m/z, 339.1143).

Pivaldehyde tosyl hydrazone sodium salt: Isolated as a white solid,u_(max) (KBr disc)/cm⁻¹ 2960, 1244, 1136, 1095; d_(H) (D₂O) 0.97 (9H,s),2.41 (3H,s), 7.22 (1H,s), 7.30 (2H,d, J 8), 7.64 (2H,d, J 8); d_(C)(D₂O) 20.4 (q), 26.9 (q), 33.6 (s), 126.4 (d), 129.2 (d), 140.5 (s),142.3 (s), 159.1 (d); m/z (FAB) 277 (M⁺+1,73%); (Found [M+H]⁺ 277.0982.C₁₂H₁₈N₂O₂SNa requires m/z, 277.0987).

Acetophenone tosyl hydrazone sodium salt: Isolated as a white solid,d_(H) (D₂O) 2.19 (3H,s), 2.25 (3H,s), 7.19-7.34 (5H,m), 7.45-7.55(2H,m), 7.74 (2H,d, J 8).

Benzaldehyde tosyl hydrazone lithium salt: This compound was preparedaccording to the above method using benzaldehyde tosyl hydrazone (3.65mmol) and lithium methoxide (prepared in situ from lithium and anhydrousmethanol). The salt was isolated as an off-white solid which appearedless stable at room temperature than the corresponding sodiumderivative. It was, however, stable for long periods of time if storedat +4° C., u_(max) (KBr disc)/cm⁻¹ 3060, 1238, 1132, 1088, 1034; d_(H)(D₂O) 2.24 (3H,s), 7.19-7.35 (5H,m), 7.41-7.54 (2H,m), 7.70 (2H,d, J8.5), 7.93 (1H,s); m/z (FAB) 281 (M⁺+1, 35%), 160 (100).

Benzaldehyde tosyl hydrazone tetrabutylammonium salt: This compound wasprepared according to the above method using benzaldehyde tosylhydrazone (10.9 mmol) and a commercially available 1M solution oftetrabutylammonium hydroxide in methanol. The salt was isolated as anoff-white solid. The compound appeared somewhat unstable at roomtemperature and was thus stored at −20° C., u_(max) (KBr disc)/cm⁻¹2961, 1248, 1129, 1073, 1044; d_(H) 0.89 (12H,t, J 7.5), 1.25-1.57(16H,m), 2.28 (3H,s), 3.10-3.19 (8H,m), 6.95-7.35 (6H,m), 7.46 (2H,d, J8.8), 7.82 (2H,d, J 8.8); d_(C) (D₂O) 13.7 (q), 19.7 (t), 21.3 (q), 24.0(t), 58.5 (t), 124.7 (d), 125.5 (d), 127.0 (d), 127.9 (d), 128.4 (d),138.6 (s), 138.8 (s), 138.9 (d), 143.6 (s); m/z (FAB) 758([M+H]⁺+NBu₄,100%), 516 (M⁺+1, 15%).

General Epoxidation Procedure Using Benzaldehyde Tosyl Hydrazone SodiumSalt and Achiral Sulphides

To a rapidly stirred solution of tetrahydrothiophene (20 mol %, 5.8 mg,0.066 mmol), rhodium (II) acetate dimer (1 mol %, 1.5 mg, 0.003 mmol),benzyltriethylammonium chloride (20 mol %, 15 mg, 0.066 mmol) and analdehyde (0.33 mmol) in anhydrous acetonitrile (1 cm³) was added thetosyl hydrazone salt (1.5 equivalents, 147 mg, 0.495 mmol). Theheterogeneous mixture was stirred rapidly at room temperature tofacilitate even dispersion of the solid, then heated at 45° C. (bathtemperature) for 3-5 hours (or until TLC showed that all of the aldehydehad been consumed). The mixture was then cooled and ethyl acetate/water(0.5 cm³+0.5 cm³) added. The organic phase was removed and the aqueousphase extracted with ethyl acetate (2×0.5 cm³). The combined organicextracts were then dried over sodium sulphate, filtered and concentratedin vacuo. The residue was purified on silica, eluting with 0-25%DCM/petrol, to give the desired epoxide.

Stilbene oxide: Isolated as a white solid (62 mg, 95%) and as a >98:2mixture of trans:cis diastereoisomers, R_(f)=0.70 (10% EtOAc/petrol);d_(H) trans isomer 3.85 (2H,s), 7.16-7.37 (10H,m); cis isomer 4.28(2H,s), 7.01-7.15 (10H,m).

2-(4-Chlorobenzenyl)-3-phenyl oxirane: Isolated as a white solid (66 mg,86%) and as a >98:2 (trans:cis) mixture of diastereoisomers, R_(f)=0.65(10% EtOAc/petrol); d_(H) trans isomer 3.82 (1H,d, J 1.8), 3.85 (1H,d, J1.8), 7.04-7.50 (9H,m); cis isomer 4.31 (1H,d, J 4.6), 4.37 (1H,d, J4.6), 7,04-7.50 (9H,m).

2-(4-Methylbenzenyl)-3-phenyl oxirane: Isolated as a colourless oil (67mg, 97%) and as a >98:2 (trans:cis) mixture of diastereoisomers,R_(f)=0.70 (10% EtOAc/petrol); d_(H) trans isomer 2.37 (3H,s), 3.83(1H,d, J 1.5), 3.86 (1H,d, J 1.5), 7.16-7.44 (9H,m); cis isomer. 2.15(3H,s), 4.24 (2H,m), 6.89-7.40 (9H,m).

2-(4-Nitrobenzenyl)-3-phenyl oxirane: This compound was purified onsilica, eluting with 0-20% EtOAc/petrol. Isolated as a white solid (75mg, 94%) and as a single (trans) diastereoisomer, R_(f)=0.68 (30%EtOAc/petrol); d_(H) 3.85 (1H,d, J 1.9), 3.98 (1H,d, J 1.9), 7.30(7H,m), 8.30 (2H,m).

2-(4-Methoxybenzenyl)-3-phenyl oxirane: This compound was purified onsilica, eluting rapidly with 0-20% EtOAc/petrol. Isolated as acolourless oil (73 mg, 98%) and as a >98:2 (trans:cis) mixture ofdiastereoisomers, R_(f)=0.50 (10% EtOAc/petrol); d_(H) trans isomer 3.71(3H,s), 3.73 (1H,d, J 1.8), 3.78 (1H,d, J 1.8), 6.93-7.41 (9H,m); cisisomer. 3.61 (3H,s), 4.23 (1H,d, J 1.6), 4.24 (1H,d, J 1.6), 6.81-7.40(9H,m).

2-n-Butyl-3-phenyl oxirane: Isolated as a colourless oil (34 mg, 59%)and as a 70:30 mixture (trans:cis) of diastereoisomers, R_(f)=0.30 (10%EtOAc/petrol); d_(H) trans isomer 0.75-1.01 (3H,m), 1.11-1.74 (6H,m),2.86 (1H,dt, J 5.5 and 2.1), 3.52 (1H,d, J 2.1), 7.01-7.35 (5H,m); cisisomer 0.75-1.01 (3H,m), 1.11-1.74 (6H,m), 3.17 (1H,m), 4.05 (1H,d, J4.2), 7.01-7.35 (5H,m).

2-Cyclohexyl-3-phenyl oxirane: Isolated as a colourless oil (46 mg, 69%)and as a 65:35 mixture (trans:cis) of diastereoisomers, R_(f)=0.41 (10%EtOAc/petrol); d_(H) trans isomer 0.76-2.09 (11H,m), 2.76 (1H,dd, J 6.8and 2.1), 3.68 (1H,d, J 2.1), 7.15-7.23 (5H,m); cis isomer 0.76-2.09(11H,m), 2.86 (1H,dd, J 8.9 and 4.2), 4.05 (1H, J 4.2), 7.15-7.23(5H,m).

2-(trans-2-Phenylethylene)-3-phenyl oxirane: This compound was purifiedon silica, eluting rapidly with 0-20% EtOAc/petrol. Isolated as acolourless oil (71 mg, 97%) and as a single (trans) diastereoisomer,R_(f)=0.42 (10% EtOAc/petrol); d_(H) 3.52 (1H,dd, J 8 and 2), 3.88(1H,dd, J 2), 6.06 (1H,dd, J 16 and 8), 6.72 (1H,d, J 16), 7.15-7.50(10H,m).

3-(3-Phenyl-oxirane)-pyridine: This compound was purified on silica,eluting with 0-50% EtOAc/petrol. Isolated as a colourless oil (46 mg,71%) and as a single, trans, diastereoisomer, R_(f)=0.37 (50% EtOAc,petrol); d_(H) 3.87 (2H,m), 7.12-7.50 (6H,m), 7.55-7.75 (1H,m), 8.59(2H,m); d_(C) 60.7 (d), 62.8 (d), 123.5 (d), 125.5 (d), 128.7 (d), 132.7(d), 136.4 (s), 140.0 (s), 147.8 (d), 149.7 (d).

2-t-Butyl-3-phenyl oxirane: This compound was prepared according to theabove general method using pivaldehyde tosyl hydrazone sodium salt(0.495 mmol, 137 mg). The epoxide was isolated as a colourless oil (4mg, 6%) and as a single (trans) diastereoisomer, R_(f)=0.64 (10%EtOAc/petrol); d_(H) 0.94 (9H,s), 2.69 (1H,m), 3.66 (1H,m), 7.01-7.35(5H,m).

2,3-Diphenyl-2-methyl oxirane: This compound was prepared according tothe above general method using acetophenone tosyl hydrazone sodium salt(0.495 mmol, 153 mg) and copper (II) acetylacetonate (5 mol %, 5 mg).The reaction was carried out at 55° C. The epoxide was isolated as awhite solid (16 mg, 18%) and as a single diastereoisomer, R_(f)=0.45(10% EtOAc/petrol); d_(H) 1.80 (3H,s), 4.23 (1H,s), 7.05-7.55 (10H,m).

Epoxidation Using Ketones as Substrates

The reactions were carried out according to the above general methodusing pentamethylene sulphide (20 mol %, 0.066 mmol, 7 mg).

2-(4-Nitrobenzenyl)-2-methyl-3-phenyl oxirane: Isolated as a pale yellowsolid (72 mg, 69%) and as a single (trans) diastereoisomer, R_(f)=0.58(20% EtOAc/petrol); d_(H) 1.78 (3H,s), 4.25 (1H,s), 6.95-7.45 (7H,m),8.05 (2H,m).

Epoxide derived from cyclohexanone: Isolated as a colourless oil; theproduct was impure and the yield was estimated by NMR analysis as 54% .Only the trans isomer was observed; R_(f)=0.78 (10% EtOAc/petrol); d_(H)1.15-2.05 (10H,m), 3.82 (1H,s), 7.15-7.40 (5H, m).

2,3-Diphenyl-2-methyl oxirane: Isolated as a colourless oil; the productwas impure and the yield was estimated by NMR analysis as 15%. Only thetrans isomer was observed. The data for this compound is reported above.

Epoxidation Using Substituted Aryl Tosyl Hydrazone Sodium Salts

The reactions were carried out according to the above general procedureusing the appropriate substituted aryl tosyl hydrazone sodium salts(prepared as described above, 0.495 mmol) and benzaldehyde (0.33 mmol).

2-(4-Chlorobenzenyl)-3-phenyl oxirane: Isolated as a white solid (72 mg,95%) and as a >98:2 (trans:cis) mixture of diastereoisomers. The NMRdata for this compound is reported above.

2-(4-Methylbenzenyl)-3-phenyl oxirane: Isolated as a colourless oil (50mg, 73%) and as a 80:20 mixture (trans:cis) of diastereoisomers. The NMRdata for this compound is reported above.

2-(4-Methoxybenzenyl)-3-phenyl oxirane: This compound was purified onsilica, eluting rapidly with 0-20% EtOAc/petrol. Isolated as acolourless oil (71 mg, 96%) and as a 67:33 mixture (trans:cis) ofdiastereoisomers. The NMR data for this compound is reported above.

2-(4-Cyanobenzenyl)-3-phenyl oxirane: Isolated as a colourless oil (65mg, 89%) and as a single (trans) diastereoisomer, R_(f)=0.69 (10%EtOAc/petrol); d_(H) 3.75 (1H,d, J 1.75), 3.85 (1H,d, J 1.75), 7.10-7.71(9H,m).

2-(2,4,6-Trimethylbenzenyl)-3-phenyl oxirane: Isolated as a colourlessoil (13 mg, 17%) and as a single (trans) diastereoisomers, R_(f)=0.53(15% EtOAc/petrol), m.p. 66-68° C.; (Found C, 85.45; H, 7.58. C₁₇H₁₈Orequires C, 85.6; H, 7.6%); u_(max) (KBr disc)/cm⁻¹ 2971, 2918, 1607,890, 792; d_(H) 2.28 (3H,s), 2.41 (6H,s), 3.82 (1H,d, J 2.1), 3.90(1H,m), 6.86 (2H,s), 7.29-7.54 (5H,m); d_(C) 19.9 (q), 21.0 (q), 60.0(d), 62.1 (d), 125.5 (d), 128.3 (d), 128.6 (d) 128.7 (d), 131.0 (s),137.1 (s), 137.5 (s); m/z (EI) 238 (M⁺, 26%), 132 (100), 117 (97), 223(48).

2-(3-Nitrobenzenyl)-3-phenyl oxirane: Isolated as an oil (contaminatedwith unreacted benzaldehyde). Yield estimated by NMR analysis 74%. Onlythe trans isomer was observed. R_(f)=0.52 (10% EtOAc/petrol); d_(H) 3.81(1H,d, J 1.9), 3.94 (1H,d, J 1.9), 7.10-7.68 (7H,m), 8.12 (2H,m).

Epoxidation Using Benzaldehyde Tosyl Hydrazone Lithium Salt

The reaction was carried out according to the above general procedureusing benzaldehyde tosyl hydrazone lithium salt (prepared as describedabove, 2.5 equivalents, 0.825 mmol, 231 mg), copper (II) acetylacetonate(5 mol %, 5 mg) and 4-chlorobenzaldehyde (47 mg, 0.33 mmol). Thereaction mixture was homogeneous during the experiment. The epoxide wasisolated as a white solid (41 mg, 54%) and as a 2.8:1 (trans:cis)mixture of diastereoisomers. The NMR data for this compound is reportedabove.

Epoxidation Using Benzaldehyde Tosyl Hydrazone Tetrabutylammonium Salt

The reaction was carried out according to the above general procedureusing benzaldehyde tosyl hydrazone tetrabutylammonium salt (prepared asdescribed above, 255 mg), copper (II) acetylacetonate (5 mol %, 5 mg)and 4-chlorobenzaldehyde (47 mg, 0.33 mmol). The reaction mixture washomogeneous during the experiment. The epoxide was isolated as a whitesolid (45 mg, 60%) and as a >98:2 (trans:cis) mixture ofdiastereoisomers. The NMR data for this compound is reported above.

Epoxidation Using Aqueous Acetonitrile as Solvent System

The reaction was carried out according to the above general procedureusing copper (II) acetylacetonate (5 mol %, 5 mg) and4-chlorobenzaldehyde (47 mg, 0.33 mmol) in water/acetonitrile (0.5cm³+0.5 cm³). The reaction mixture was homogeneous in this solventsystem.

Benzaldehyde tosyl hydazone sodium salt (3 equivalents, 1 mmol, 296 mg)gave the epoxide as a white solid (68 mg, 89%) and as a 2.6:1 mixture(trans:cis) of diastereoisomers.

Benzaldehyde tosyl hydrazone lithium salt (2.5 equivalents, 0.825 mmol,231 mg) gave the epoxide as a white solid (66 mg, 86%) and as a 2.8:1mixture (trans:cis) of diastereoisomers. The NMR data for the epoxide isreported above.

Preparation of a Sulphide of Formula (D) Wherein R^(a) is CH₂OCH₃ andR^(b) is H

(10)-Mercaptoisoborneol and (10)-mercaptoborneol were prepared bymodifying the procedure of Eliel (J. Org. Chem. 1979, 44, 3598).

A solution of (+)-(10)-camphorsulphonyl chloride (commercial material,purified by recrystallisation from DCM/hexane) (2.56 g, 10.21 mmol) inanhydrous diethyl ether (50 cm³) was added dropwise to a stirredsuspension of lithium aluminium hydride (1.94 g, 51.11 mmol) inanhydrous diethyl ether (50 cm³) at 0° C. over 1 hour. Once the additionwas complete, stirring was continued for a further 2 hours at 0° C. Themixture was then allowed to warm to room temperature and refluxed for afurther 4 hours. The reaction mixture was then allowed to cool to roomtemperature. Excess hydride was quenched by the cautious addition oficed water followed by dilute HCl (aq.) (20 cm³). Rochelle's salt wasthen added (5.0 g) and stirring continued for 5 minutes beforefiltration through CELITE™. The aluminium residues were then washed withcopious quantities of diethyl ether. The filtrate was washed with water(3×50 cm³) and brine (3×50 cm³) then dried over magnesium sulfate.Removal of the solvent in vacuo gave the crude product which waspurified on silica, eluting with 98:2 petrol/EtOAc.(10)-Mercaptoisoborneol was obtained as a waxy solid (1.13 g, 59%),[a]²⁰ _(D)−56.2 (c 5.1, CHCl₃); d_(H) 0.83 (3H,s), 1.05 (3H,s), 1.28(1H,dd, J 6 and 10), 0.95-1.80 (7H,m), 1.95 (1H,brs), 2.56 (1H,dd, J 12and 6), 2.79 (1H,dd, J 12 and 10), 3.97-4.04 (1H,m).(10)-mercaptoborneol was eluted second as a white solid (250 mg, 13%),[a]²⁰ _(D)−13.1 (c 9, CHCl₃); (Found: C, 64.44; H, 9.66; S, 17.16.C₁₀H₁₈OS requires C, 64.5; H, 9.7; S, 17.2%); d_(H) 0.80-2.36 (9H,m),0.90 (6H,s), 2.52 (1H,dd, J 10 and 10), 2.73 (1H,dd, J 10 and 7),4.31-4.39 (9H,m).

To a cooled solution (0° C.) of (+)-(10)-mercaptoisoborneol (0.52 g,2.80 mmol) and methoxyacetaldehyde dimethyl acetal (1.05 cm³, 8.39 mmol)in dichloromethane (6 cm³) under nitrogen or argon, was added borontrifluoride etherate (0.39 cm³, 3.08 mmol). After a few minutes thereaction mixture was loaded directly onto a silica gel column and elutedwith 50% DCM/petrol to give the oxathiane as a pale yellow oil (637 mg,94%), R_(f)=0.83 (20% EtOAc/petrol); [a]²⁰ _(D)−126.1 (c 1.11, CHCl₃);u_(max) (film)/cm⁻¹ 2940, 2872, 1121, 1067; d_(H) 0.78-2.00 (13H,m),2.75 (1H,d, J 14), 3.09 (1H, , J 14), 3.38 (3H,s), 3.46 (1H,dd, J 10.5and 4), 3.58 (2H,m), 4.90 (1H,dd, J 7 and 4); d_(C) 20.4 (q), 23.2 (q),27.3 (t), 28.3 (t), 34.4 (t), 37.9 (t), 42.5 (s), 45.5 (d), 46.7 (s),59.4 (q), 74.8 (t), 80.7 (d), 85.2 (d), m/z (EI) 242 (M⁺, 13%), 197(100), 135 (70), 93 (27); (Found [M]⁺ 242.1344. C₁₃H₂₂O₂S requires m/z,242.1341).

General Procedure for Epoxidation Using Benzaldehyde Tosyl HydrazoneSodium Salt and a Sulphide of Formula (D) Wherein R^(a) is CH₂OCH₃ andR^(b) is H

To a rapidly stirred solution of a sulphide of formula (D) wherein R^(a)is CH₂OCH₃ and R^(b) is H (1 equivalent, 80 mg, 0.33 mmol), rhodium (II)acetate dimer (1 mol %, 1.5 mg, 0.003 mmol), benzyltriethylammoniumchloride (20 mol %, 15 mg, 0.066 mmol) and benzaldehyde (35 mg, 0.33mmol) in anhydrous acetonitrile (1 cm³) was added the tosyl hydrazonesalt (1.5 equivalents, 147 mg, 0.495 mmol). The heterogeneous mixturewas stirred rapidly at room temperature to facilitate even dispersion ofthe solid, then held at 30° C. (bath temperature) for 32 hours. Themixture was then cooled and ethyl acetate/water (0.5 cm³+0.5 cm³) added.The organic phase was removed and the aqueous phase extracted with ethylacetate (2×0.5 cm³). The combined organic extracts were then dried oversodium sulphate, filtered and concentrated in vacuo. The residue waspurified on silica, eluting with 0-25% DCM/petrol, to give stilbeneoxide as a white solid (38 mg, 59%) and as a >98:2 mixture (trans:cis)of diastereoisomers; enantiomeric excess 93% (R, R major) as determinedby chiral HPLC (see conditions below). The NMR data for this compound isreported above.

Determination of Enantiomeric Excess

Column 25 cm, 4.6 mm internal diameter, stainless steel column packedwith chiracell OD stationary phase.

Mobile phase 1% iso-propyl alcohol/99% petroleum ether (40-65° C.).

Flow rate 2 cm³ min⁻¹

Temperature Ambient

Detection 254-240 nm

Standard A racemic sample was run to check the retention times of theenantiomers. The chromatogram was recorded using a diode array detectorto confirm the physical relationship between the enantiomers.

Retention Major enantiomer (R, R) 5.99 minutes. [Absolute configuration

times determined by comparison of [a]_(D) with literature values (see J.Org. Chem. 1979, 44, 2505).] Minor enantiomer (S, S) 4.52 minutes.

Following the above process and using the same substrates, except thatdifferent sulphides of formula (D) were used, gave the followingresults.

Isolated yield selectivity R^(a) R^(b) epoxide trans:cis ee Comments CH₃H <5% >98:2 90% CH₂OCH₃ H 56% >98:2 94% Room temperature, 3 daysCH₂O(CH₂)₃CH₃ H 27% >98:2 OCOCH₃ H 22% >98:2

Cyclopropanation of Chalcone Using Benzaldehyde Tosyl Hydrazone SodiumSalt

To a rapidly stirred solution of pentamethylene sulphide (1 equivalent,0.10 cm³,1 mmol), rhodium (II) acetate dimer (1 mol %, 4 mg, 0.01 mmol),benzyltriethylammonium chloride (20 mol %, 45.5 mg, 0.2 mmol) and transchalcone (208 mg, 1 mmol) in anhydrous acetonitrile (3 cm³) was addedthe tosyl hydrazone salt (1.5 equivalents, 440 mg, 1.5 mmol). Theheterogeneous mixture was stirred rapidly at room temperature tofacilitate even dispersion of the solid, then heated at 45° C. (bathtemperature) for 22 hours. The mixture was then cooled and ethylacetate/water (5 cm³+5 cm³) added. The organic phase was removed and theaqueous phase extracted with ethyl acetate (2×5 cm³). The combinedorganic extracts were then dried over sodium sulphate, filtered andconcentrated in vacuo. The residue was purified on silica, eluting with0-50% DCM/petrol, to give the cyclopropane as a white solid (131 mg,44%) and as a 70:30 mixture (trans:cis) of diastereoisomers, m.p.(mixture) 144-146° C.; d_(H) trans isomer: 3.28 (1H,dd, J 7 and 5.5),3.38 (1H,dd, J 9.5 and 7), 3.65 (1H dd, J 9.5 and 5.5), 7.01-7.65(13H,m), 7.95 (2H,m); cis isomer: 3.33 (2H,d, J 5.5), 3.55 (1H,t, J5.5), 7.01-7.65 (13H,m) 8.20 (2H,m).

Aziridination of N-Benzylidenetoluene-p-sulphonamide Using BenzaldehydeTosyl Hydrazone Sodium Salt

To a rapidly stirred solution of tetrahydrothiophene (1 equivalent, 0.34mmol, 0.03 cm³), rhodium (II) acetate dimer (1 mol %, 1.5 mg, 0.003mmol), benzyltriethylammonium chloride (20 mol %, 15 mg, 0.066 mmol) andimine (89 mg, 0.33 mmol) in anhydrous acetonitrile (1 cm³) was added thetosyl hydrazone salt (1.5 equivalents, 147 mg, 0.495 mmol). Theheterogeneous mixture was stirred rapidly at room temperature tofacilitate even dispersion of the solid, then heated at 45° C. (bathtemperature) for 3 hours . The mixture was then cooled and ethylacetate/water (0.5 cm³+0.5 cm³) added. The organic phase was removed andthe aqueous phase extracted with ethyl acetate (2×0.5 cm³). The combinedorganic extracts were then dried over sodium sulphate, filtered andconcentrated in vacuo. The residue was purified on silica, eluting with0-25% EtOAc/petrol, to give the aziridine as a white solid (63 mg, 96%)and as a 3:1 (trans:cis) mixture of diastereoisomers, cis isomerR_(f)0.32 (10% EtOAc/petrol); m.p. 153-154° C.; d_(H) 2.42 (3H,s), 4.21(2H,s), 7.00-7.10 (10H,m), 7.34 (2H,d, J 8), 7.98 (2H,d, J 8); transisomer R_(f)0.30 (10% EtOAc/petrol); m.p. 138° C.; d_(H) 2.38(3H,s),4.24(2H,s), 7.22(2H,d, J 8), 7.30-7.44(10H,m), 7.60(2H,d, J 8).

In Situ Epoxidation Using a Sulphide of Formula (J) Wherein R′ isHydrogen

Cuprous bromide (7 mg, 0.05 mm, 10 mol %) was placed in a vial underargon and a sulphide of formula (J) wherein R′ is hydrogen (11 mg, 0.05mmol, 10 mol %) in DCM (1 cm³) added. A green solution formed which wasstirred at room temperature for 2 hours before the solvent was removedby a steady stream of argon. The residue was dissolved in acetonitrile(1.5 cm³) and 4-chlorobenzaldehyde (70 mg, 0.5 mmol) added.Benzyltriethylammonium chloride (23 mg, 0.1 mmol, 20 mol %) was addedfollowed by benzaldehyde tosyl hydrazone sodium salt (0.75 mmol, 222mg). The rapidly stirring mixture was heated to 40° C. overnight. Theepoxide produced was purified by column chromatography (10% DCM/petrol)and furnished as a white solid (56 mg, 49%) and as a single (trans)diastereoisomer. The NMR data for this compound is reported above.

Preparation of (1S, 4R)-10-Mercaptomethyl-7,7-dimethyl-bicyclo[2.2.1]heptan-2-one 1

(+)-(10)-Camphorsulfonyl chloride (12.0 g, 48 mmol), andtriphenylphosphine (50.1 g, 191 mmol) were refluxed in a mixture ofwater (40 mL) and 1,4-dioxane (160 mL) for one hour under nitrogen.After the reaction mixture had cooled it was extracted with petrol (200mL and 3×100 mL). The combined organic extracts were washed with water(2×100 mL) and brine (100 mL) before drying over MgSO₄. After filtrationand removal of the solvents under reduced pressure, the resulting oilwas loaded directly onto a silica gel column and eluted with 5% ethylacetate in petrol to give thiol 1 as a white crystalline solid (7.3 g,82%), m.p. 62-65° C. [Lit., 65-66° C.]; d_(H) (250 MHz; CDCl₃) 0.89 (3H,s, CH₃), 1.00 (3H, s, CH₃), 1.21-2.01 (6H, m), 2.07 (1H, t, J 4.6),2.26-2.43 (2H, CHHS, (CO)CHH), 2.85 (1H, dd, J 13.7, 6.7, CHHS), [lit.,d_(H) (CCl₄) 0.93 (3H, s), 1.05 (3H, s), 1.2-2.6 (8H, m), 2.73 (1H, d, J6), 2.95 (1H, d, J 6)]; d_(C) (63 MHz; CDCl₃) 19.83 (CH₃), 20.31 (CH₃),21.40 (CH₂), 26.63 (CH₂), 27.06 (CH₂), 29.92 (C), 43.29 (CH₂), 43.67(CH), 47.85 (C), 60.65 (C).

Preparation of (1S, 2S,4R)-1-Mercaptomethyl-7.7-dimethyl-2-(trimethyl-silanylethynyl)-bicyclo[2.2.1]heptan-2-ol 2

Trimethylsilylacetylene (0.15 mL, 1.1 mmol) was added dropwise to a −78°C. solution of butyllithium (0.32 mL of a 2.5M solution in hexanes) intetrahydrofuran (0.5 mL) under nitrogen. After thirty minutes a solutionof 1 (50 mg, 0.27 mmol) in tetrahydrofuran (0.5 mL) was added to thereaction mixture and the resulting solution stirred for three hours at−78° C. The reaction mixture was warmed to room temperature before beingquenched with saturated ammonium chloride solution. The organic phasewas separated and the aqueous phase extracted with ethyl acetetatebefore drying the combined organic phases over MgSO₄. After filtrationand removal of the solvents, the desired alcohol 2 was obtained (65 mg,84%), [a]²⁰ _(D)+9.3 (c 2.68 in CHCl₃); u_(max) (thin film)/cm⁻¹ 3462(OH), 2956 (CH), 2161 (SH), 842 (TMS); d_(H) (250 MHz; CDCl₃) 0.08-0.21(9H, m SiCH₃), 0.90 (3H, s, CH₃), 1.60 (3H, s, CH₃), 0.77-1.29 (3H, m),1.49-183 (4H,m), 2.12-2.42 (2H, m), 2.53 (1H, dd, J 13.0, 7.5, CHHS),3.01 (1H, dd, J 13.0, 7.0, CHHS); d_(C) (63 MHz; CDCl₃) −0.24 (CH₃),20.82 (CH₃), 21.63 (CH₃), 23.40 (CH₂), 26.51 (CH₂), 29.35 (CH₂), 45.84(CH), 49.53 (C), 49.72 (CH₂), 56.30 (C), 89.91 (C), 11.27 (C),quaternary not visible; m/z (EI) 282 (M⁺, 46%), 233 (27), 108 (52), 73(100), (Found; M⁺, 282.1472. C₁₅H₂₆OSSi requires 282.1474).

Preparation of (1S, 5R,7R)-10,10-Dimethyl4-methylene-3-thia-tricyclo[5.2.1.0^(1,5)]decan-5-ol 3

Tetrabutylammonium fluoride (0.5 mL of a 1.0M solution intetrahydrofuran) was added to a solution of alcohol 2 (65 mg, 0.23 mmol)in tetrahydrofuran (5 mL) under nitrogen. After two hours water wasadded to the solution and the resulting mixture extracted withdichloromethane. The combined organic extracts were washed with brineand dried over MgSO₄. After filtration and removal of the solvents underreduced pressure, chromatography with 5% ethyl acetate in petrol gavesulfide 3 (31 mg, 64%), [a]²⁰ _(D)−90.5 (c 2.10 in CHCl₃); u_(max) (thinfilm)/cm⁻¹ 3483 (OH), 2942 (CH), 1701 (C═C), 1627 (C═C); d_(H) (250 MHz;CDCl₃) 0.97 (3H, s, CH₃), 1.01-1.16 (1H, m), 1.27 (3H, s, CH₃),1.50-1.83 (4H, m), 1.96-2.10 (2H, m), 2.14 (1H, br s, OH), 2.52 (1H, d,J 9.0, CHHS), 3.22 (1H, d, J 9.0, CHHS), 4.93 (1H, d, J 1.0, ═CHH), 5.12(1H, d, J 1.0, ═CHH); d_(C) (63 MHz; CDCl₃) 22.02 (CH₃), 22.05 (CH₃),26.89 (CH₂), 31.95 (CH₂), 32.07 (CH₂), 37.38 (CH₂), 46.25 (C), 50.79(CH), 61.68 (C), 93.20 (C), 101.39 (CH₂), 151.81 (C); m/z (EI) 210 (M⁺,30%), 108 (57), 95 (100), 81 (27), (Found; M⁺, 210.1085. C₁₂H₁₈OSrequires 210.1078).

Preparation of (1S, 5R,7R)-10,10-Dimethyl-4-methylene-3-thia-5-trimethylsilyloxy-tricyclo[5.2.1.0^(1,5)]decan4

A mixture of N-trimethylsilylimidazole (1.71 mL, 11.6 mmol) and alcohol3 (95 mg, 0.45 mmol) were heated at 100° C. for 90 minutes undernitrogen. After cooling at room temperature the mixture was diluted withpetroleum ether, washed with water and dried over MgSO₄. Afterfiltration and removal of the solvents under reduced pressure,chromatography with petrol gave sulfide 4 (120 mg, 94%), u_(max) (thinfilm)/cm⁻¹ 2941 (CH), 1622 (C═C), 1247 (SiCH₃), 1082 (SiO); d_(H) (250MHz; CDCl₃) 0.10 (s, 9H), 0.94 (s, 3H), 1.22 (s, 3H), 0.80-1.10 (m, 1H),1.20-2.05 (m, 6H), 2.36-2.39 (d, J8.5, 1H), 3.24-3.27 (d, J8.3, 1H),4.93 (s, 1H), 5.07 (s, 1H); d_(C) (63 MHz; CDCl₃) 1.7 (CH₃), 22.2 (CH₃),22.6 (CH₃), 26.7 (CH₂), 31.1 (CH₂), 32.3 (CH₂), 39.1 (CH₂), 46.1 (C),51.0 (CH), 62.8 (C), 94.1 (C), 102.0 (CH₂), 152.7 (C); m/z (EI) 282 (M⁺,100%), 267 (75).

Epoxidation of Benzaldehyde Using Sulfides 3 and 4

To a rapidly stirred solution of sulfide, rhodium (II) acetate dimer (1mol %, 1.5 mg, 003 mmol), benzyltriethylammonium chloride (20% mmol, 15mg, 0066 mmol) and benzaldehyde (0.034 mL, 0.33 mmol) in anhydrousacetonitrile (1 mL) was added benzaldehyde tosyl hydrazone sodium salt(147 mg, 0.495 mmol). The mixture was stirred at 30° C. for 40 hours.The mixture was then cooled and ethyl acetate/water added. The aqueousphase was extracted with ethyl acetate and the combined organic extractsdried with sodium sulfate, filtered and concentrate in vacuo. Theresidue was purified on silica with 20% DCM/petrol to give the epoxide.

Sulfide mmol sulfide yield (%) e.e.(%) trans/cys 3 0.33 23 63 55/45 40.06 78 76 85/15

N,N′-Dimethyl Isopulegol Dithiocarbamate

To a solution of (−)-isopulegol (1.0 g, 6.48 mmol) in THF (10 ml) atroom temperature was added sequentially triphenylphosphine (4.42 g, 2.6eq, 16.86 mmol) and zinc N,N′-dimethyldithiocarbamate (1.98 g, 1.0 eq,6.48 mmol). The white mixture was then cooled to 0° C. and diethylazodicarboxylate (2.86 ml, 2.8 eq, 18.15 mmol) was added dropwise over10 minutes. The mixture was slowly warmed to room temperature andstirred for 24 hours, after which time it was diluted with ethyl acetate(50 ml) and suction filtered through a pad of silica. Solvent removaland purification by flash column chromatography (0→2.5% v/v ethylacetate/hexane) afforded the product as a light beige solid (1.36 g,82%). Recrystallisation from hexane gave clear crystals; d_(H) (250 MHz,CDCl₃) 4.82 (1H, obs sextet, J 1.5, CHS), 4.68-4.64 (2H, m, vinyl H),3.54 (3H, s, NCH₃), 3.37 (3H, s, NCH₃), 2.31 (1H, br d, J 12.2, CHHS),2.13 (1H, ddd, J 13.7, 5.5 and 3.4, CHHS), 1.90-1.63 (3H, m), 1.77 (3H,s, CH₃), 1.49-1.32 (2H, m), 1.11-096 (1H,m), 0.91 (3H, d, J 6.7, CH₃).

Isopulegol Thiol

To a solution of dithiocarbamate (2.69 g, 10.47 mmol) in ether (15 ml)at 0° C. was added lithium aluminium hydride (994 mg, 2.5 eq, 26.17mmol). The mixture was warmed to room temperature and then refluxed for24 hours. At 0° C., saturated sodium sulfate solution was cautiouslyadded until the mixture was a white colour. This suspension was thensuction filtered (ether washings, 3×30 ml). Solvent removal andpurification by flash column chromatography (petrol) afforded theproduct as a clear oil (1.62 g, 90%); d_(H) (250 MHz, CDCl₃) 4.90 (1H,m, vinyl H), 4.71 (1H, m, vinyl H), 3.63 (1H, m, CHS), 2.18-2.12 (1H,m), 1.96-1.71 (4H, m), 1.74 (3H, s, CH₃), 1.55-1.42 (2H, m), 1.33 (1H,obs dd, J 4.8 and 1.1), 1.04-0.84 (1H, m), 0.90 (3H, d, J 6.1, CH₃).

Isopulegol-derived Sulfide

A mixture of isopulegol thiol (850 mg, 5.0 mmol) andazo-bisisobutyronitrile (82 mg, 0.10 eq, 0.50 mmol) in benzene (50 ml)was refluxed under nitrogen for 15 hours. Solvent removal andpurification by flash column chromatography (0.5% v/v ether/hexane)afforded the product as a clear oil (800 mg, 94%) (92:8 ratio ofdiastereomers); d_(H) (250 MHz, CDCl₃) 3.80 (1H, br s, CHS), 2.85 (1H,dd, J 10.1 and 7.3, CHHS), 2.59 (1H, obs t, J 10.1, CHHS), 2.40-2.22(1H, m), 1.96-1.66 (4H, m), 1.51-1.24 (4H, m), 1.02 (3H, d, J 6.7, CH₃),0.87 (3H, d, J 6.4, CH₃).

Application of this sulfide in the in situ epoxidation cycle (0.33 mmolscale, 1.0 eq benzaldehyde, 1 mol % Rh₂(OAc)₄, 20 mol % sulfide, 20 mol% BnEt₃N⁺Cl⁻, 1.5 eq benzaldehyde tosylhydrazone sodium salt, MeCN (0.33M in PhCHO), 30-35° C., 40 hours) gave stilbene oxide as a white solid(88% yield) and as a 90:10 mixture (trans:cis) of diastereomers by ¹HNMR and 19% ee (S,S major) by chiral GC (a-CD column, 20 psi, 180° C.isothermal).

(2R,5R)-(+)-2,5-Dimethyldithiolane

This sulfide was prepared according to the literature procedure(Tetrahedron: Asymmetry, 1998, 9, 189). Application of this sulfide inthe in situ epoxidation cycle (conditions as shown above) gave stilbeneoxide as a white solid (60% yield) and as a 90:10 mixture (trans:cis) ofdiastereomers by ¹H NMR and 41% ee (S,S major) by chiral HPLC (ODcolumn, 1% ^(i)PrOH/hexane, 2 ml/min).

(R)-(+)-bis(Methylthio)-1,1′-binaphthalene

This sulfide was prepared according to the literature procedure (J. Org.Chem., 1993, 58, 1748). Application of this sulfide in the in situepoxidation cycle (conditions as shown above, except MeCN/THF (3:1)solvent mixture) gave stilbene oxide as a white solid (78% yield) and asa 95:5 mixture (trans:cis) of diastereomers by ¹H NMR and 11% ee (R,Rmajor) by chiral GC (a-CD column, 20 psi, 180° C. isothermal).

(1R,2S,4R,5S)-2,5-Dimethyl-thiabicyclo[2.2.1]heptane

To a solution of (+)-2,5-dimethylcyclohexane-1,4-diolbis(methanesulfonate) (prepared according to the literature procedure:Organometallics, 1991, 10, 3449) (1.19 g, 5.8 mmol) in DMSO (25 ml) atroom temperature was added sodium sulfide (469 mg, 1.0 eq, 6.0 mmol).The green solution was heated to 120° C. for 7 hours and then cooled toroom temperature overnight. The mixture was poured into a water/icesolution and extracted with pentane (3×25 ml). The combined organicswere dried (MgSO₄), concentrated in vacuo and purified by flash columnchromatography (pentane) to afford the crude product. Bulb-to-bulbdistillation gave the desired sulfide (158 mg, 19%); d_(H) (250 MHz,CDCl₃) 3.30 (2H, d, J 4.0), 1.77 (4H, m), 1.18 (2H, m), 0.96 (6H, d, j6.4, 2×CH₃).

Application of this sulfide in the in situ epoxidation cycle (conditionsas shown previously, except run at 22° C. and 42 hours) gave stilbeneoxide as a white solid (73% yield) and as a 92:8 mixture (trans:cis) ofdiastereomers by ¹H NMR and 18% ee (S,S major) by chiral GC (a-CDcolumn, 20 psi, 180° C. isothermal).

(1S,4R,6S)-1-Methyl 4-iso-Propene 7-Thiane 10-oxa bicyclo [4.4.0]dec-8-ene

To a 60% solution in oil of NaH (0.16 g, 3.9 mmol), in DMF (7 ml) wasadded mercaptoacetaldehyde diethyl acetal (0.55 g, 3.7 mmol) at 0° C.Then (1R,4S)-trans-limonen-1,2-epoxide (0.4 ml, 2.4 mmol) was added. Theresulting mixture was stirred overnight at room temperature thenquenched with 2N HCl and extracted with Et₂O. The combined extracts werewashed twice with 10% NaOH and brine, dried over MgSO₄, filtered and thesolvent was removed under vacuo. The residue was then dissolved in dryEt₂O (30 ml) and BF₃.Et₂O (0.9 ml, 7.2 mmol) was added at 0° C. After 3hat room temperature, the resulting mixture was quenched with a saturatedsolution of NH₄Cl, and the aqueous layer was extracted with Et₂O. Thecombined extracts were washed with brine, dried over MgSO₄ and thesolvent was removed under vacuo after filtration. The residue waspurified by chromatography through silica gel (petroleum ether/EtOAc95:5) to afford pure diene (0.41 g, 80%) as a colourless oil.

¹H NMR (CDCl₃, δppm, J Hz): 6.42 (1H, d, J 6.5, ═CHO), 4.98-4.86 (3H, m,═CH₂ and ═CHS), 3.15 (1H, dd, J 13.3, 3.5, CHS), 2.38 (1H, m, CH),2.15-2.07 (2H, m, 2CH), 1.77-1.70 (4H, m, CH₃ and CH), 1.64-1.32 (3H, m,3CH), 1.32 (3H, s, CH₃). IR (film KBr) (ν_(max)): 3084, 2940, 2870,1640, 1607, 1458, 1442, 1377, 1241, 1061, 1046, 890, 702 cm⁻¹.

(1S,4R,6S)-1-Methyl 4-iso-propyl 7-thiane 10-oxa bicyclo [4.4.0] decane

The preceding diene was dissolved in EtOH (50 ml) and a 5% PdS/C (100mg) was added. The mixture was stirred overnight under an H₂ atmosphere,then filtered through celite. The residue was purified by chromatographythrough silica gel (petroleum ether/EtOAc 95:5) to afford pure sulfide(0.33 g, 80%) as a colourless oil.

¹H NMR (CDCl₃, δppm, J Hz): 4.01 (1H, dt, J 12.3, 2.3, CHO), 3.82-3.78(1H, m, CHO), 3.07-3.02 (2H, m, CH₂S), 2.35 (1H, dt, J 13.4, 2.0, CHS),1.94-1.16 (11H, m, and CH₃), 0.89 (6H, d, J 6.6, (CH₃)₂).

IR (film KBr) (ν_(max)): 2936, 2868, 1459, 1370, 1298, 1188, 1108, 1080,630 cm⁻¹.

(2R)-2-Iso-propyl 5-methyl 3-thiane hex-5-enol

General procedure for the alkylation of the mercaptoalcohol:

To a mixture of (2R)-2-iso-propyl 1,2-mercaptoethanol (1.00 mmol) andsodium methoxide (1.13 mmol) in methanol (2 ml) was added methallylbromide (1.00 mmol) at 0° C., and the mixture was stirred at 0° C. for 1h and at 25° C. for 3h. Then, the solvent was removed under reducedpressure and the residue was filtered and washed with ether. The etherlayer was washed with brine, dried over MgSO₄ and the solvent wasevaporated under reduced pressure. The residue was purified bychromatography through silica gel (petroleum ether/Et₂O 8:2) to affordpure alkylated compound (64%) as a pale yellow oil.

¹H NMR (250 MHz, CDCl₃), δppm: 0.94-1.00 (m, 6H, (CH ₃)₂CH), 1.82 (s,3H, CH ₃C═CH₂), 1.85-2.00 (m, 1H, (CH₃)₂CH), 2.18 (bs, 1H, OH),2.48-2.55 (m, 1H, CHS), 3.06 (dd, J=13 Hz and 1 Hz, 1H, CHHS), 3.16 (dd,J=13 Hz and 1 Hz, 1H, CHHS), 3.53 (dd, J=11 Hz and 7 Hz, 1H, CHHO), 3.68(dd, J=11 Hz and 5 Hz, 1H, CHHO), 4.80-4.84 (m, 2H, C═CH ₂).

(5R)-2-Iodomethyl 2-methyl 5-iso-propyl 1,4-oxathiane

General procedure for the iodocyclisation:

To a stirred solution of the above alkylated compound (1.00 mmol) inacetonitrile (11 ml) were added anhydrous sodium carbonate (10.00 mmol)and iodine (5.00 mmol). The mixture was stirred in the dark for 8 h atroom temperature, diluted with ether and then treated with a 10% aqueoussolution of Na₂SO₃. The organic layer was separated, washed with brine,and dried over MgSO₄. Removal of the solvent under reduced pressurefollowed by chromatography of the residue through silica gel (petroleumether/Et₂O 8:2) afforded pure iodo compound (55%) as a mixture ofdiastereoisomers.

(5R)-2,2-Dimethyl 5-iso-propyl 1,4-oxathiane

General procedure for the reduction:

To a cooled solution of lithium aluminium hydride (1.00 mmol) in THF (2ml) was added dropwise a solution of the iodo compound (1.00 mmol) inTHF (3 ml). At the end of the addition, the ice bath was removed and themixture was stirred overnight. The mixture was then recooled to 0° C.and treated with a saturated solution of NH₄Cl and diluted HCl until theentire solid was dissolved. The aqueous layer was extracted with Et₂O.The combined extracts were washed with brine, dried over MgSO₄ and thesolvents were evaporated in vacuo. The residue was purified bychromatography through silica gel (petroleum ether/Et₂O 7:3) to affordpure sulfide (64%) as a pale yellow liquid.

¹H NMR (250 MHz, CDCl₃), δppm: 0.96 (d, J=6 Hz, 3H, CH ₃CH), 0.98 (d,J=6 Hz, 3H, CH ₃CH), 1.25 (s, 3H, CH₃C), 1.35 (s, 3H, CH₃C), 1.67-1.80(m, 1H, CH₃CH), 2.35 (d, J=13 Hz, 1H, CHHS), 2.55 (ddd, J=10 Hz, 6 Hzand 3 Hz, 1H, CHS), 2.71 (d, J=13 Hz, 1H, CHHS), 3.71 (dd, J=12 Hz and10 Hz, 1H, CHHO), 3.86 (dd, J=12 Hz and 3 Hz, 1H, CHHO).

(2R)-2,5-Dimethyl 3-thiane hex-5-enol

Following the general procedure for the alkylation of themercaptoalcohol, (2R)-2-methyl 1,2-mercaptoethanol gave 72% of purealkylated compound.

¹H NMR (250 MHz, CDCl₃), δppm: 1.24 (d, J=7 Hz, 3H, CH ₃CH), 1.81 (s,3H, CH ₃C═CH₂), 2.15 (bs, 1H, OH), 2.75-2.88 (m, 1H, CHS), 3.07 (dd,J=14 Hz and 1Hz, 1H, CHHS), 3.18 (dd, J=14 Hz and 1 Hz, 1H, CHHS), 3.47(dd, J=11 Hz and 6 Hz, 1H, CHHO), 3.59 (dd, J=11 Hz and 5 Hz, 1H, CHHO),4.81-4.84 (m, 2H, C═CH ₂).

(5R)-2-Iodomethyl 2,5-dimethyl 1,4-oxathiane

Following the general procedure for the iodocyclisation, the precedingcompound gave 45% of a mixture of diastereoisomers.

(5R)-2,2,5-Trimethyl 1,4-oxathiane

Reduction of the preceding iodo compound, following the generalprocedure, gave 45% of pure sulfide.

¹H NMR (250 MHz, CDCl₃), δppm: 1.13 (d, J=7 Hz, 3H, CH ₃CH), 1.39 (s,3H, CH₃C), 1.48 (s, 3H, CH₃C), 2.40 (d, J=13 Hz, 1H, CHHS), 2.80-3.00(m, 2H, CHS and CHHS), 3.57 (dd, J=12 Hz and 10 Hz, 1H, CHHO), 3.92 (dd,J=12 Hz and 3 Hz, 1H, CHHO).

What is claimed is:
 1. A process for the preparation of an oxirane,aziridine or cyclopropane of formula (I),

wherein X is oxygen, NR⁴ or CHR⁵, R¹ is hydrogen, alkyl, aryl,heteroaromatic, heterocyclic or cycloalkyl; R² is hydrogen, alkyl, aryl,heteroaromatic, CO₂R⁸, CHR¹⁴NHR¹³, heterocyclic or cycloalkyl; or R¹ andR² join together to form a cycloalkyl ring; R³ and R¹⁰ are,independently, hydrogen, alkyl, aryl, heteroaromatic, CO₂R⁸, R⁸ ₃Sn,CONR⁸R⁹, trialkylsilyl or triarylsilyl; R⁴ is an electron withdrawinggroup; R⁵ is alkyl, cycloalkyl, aryl, heteroaromatic, SO₂R⁸, SO₃R⁸,COR⁸, CO₂R⁸, CONR⁸R⁹, PO(R⁸)₂, PO(OR⁸)₂ or CN; R⁸ and R⁹ areindependently alkyl or aryl; and R¹³ and R¹⁴ are independently hydrogen,alkyl or aryl; the process comprising the steps of (a) degrading in situa compound of formula (II), (IIa), (IIb) or (IIc):

 wherein R³ and R¹⁰ are as defined above; Y is a cation; depending onthe nature of Y, r is 1 or 2; and L is a suitable leaving group, to forma diazo compound of formula (III):

 wherein R³ and R¹⁰ are as defined above; (b) reacting the compound offormula (III) with a suitable transition metal catalyst; (c) reactingthe product of step (b) with a sulphide of formula SR⁶R⁷, wherein R⁶ andR⁷ are independently alkyl, aryl or heteroaromatic, or R⁶ and R⁷ jointogether to form an optionally substituted ring which optionallyincludes an additional heteroatom; and (d) reacting the product of step(c) with a compound of formula (IV):

 wherein R¹ and R² are as defined above.
 2. A process according to claim1, wherein a compound of formula (II) is thermally decomposed in thepresence of an aprotic solvent and a phase transfer catalyst, but in theabsence of free base.
 3. A process according to claim 1, wherein thesulphide is a cyclic sulphide.
 4. A process according to claim 1,wherein the sulphide has the formula (VI):

wherein Z represents —CH₂—, O, S, —CHalkyl—, C(alkyl)₂—, or NR⁴, each ofR^(d−k) independently represents H, alkyl or alkoxyalkyl or are linkedto form a cyclic moiety, provided that at least 2 of R^(d), R^(e), R^(j)and R^(k) represent H, and R⁴ is SO₂R⁸, SO₃R⁸, COR⁸, CO₂R⁸, CONR⁸R⁹,PO(R⁸)₂, PO(OR⁸)₂ or CN, and R⁸ and R⁹ are independently alkyl or aryl.5. A process according to claim 4, wherein Z represents O.
 6. A compoundof formula (VII):

wherein R^(m) and R^(n) are each independently alkyl or alkoxyalkyl. 7.A process according to claim 2, wherein the sulphide is a cyclicsulphide.
 8. A process according to claim 7, wherein the sulphide hasthe formula (VI):

wherein Z represents —CH₂—, O, S, —CHalkyl—, C(alkyl)₂— or NR⁴, each ofR^(d−k) independently represents H, alkyl or alkoxyalkyl or are linkedto form a cyclic moiety, provided that at least 2 of R^(d), R^(e), R^(j)and R^(k) represent H, and R⁴ is SO₂R⁸, SO₃R⁸, COR⁸, CO₂R⁸, CONR⁸R⁹,PO(R⁸)₂, PO(OR⁸)₂ or CN, and R⁸ and R⁹ are independently alkyl or aryl.9. A process according to claim 8, wherein Z represents O.
 10. A processaccording to one of claims 1-5 or claims 7-9, wherein in the compound offormula (IV), X is O, R¹ is H and R² is an optionally substituted alkylgroup comprising from 1 to 10 carbon atoms; an optionally substitutedphenyl group, or an optionally substituted heteroaromatic groupcomprising a 5 or 6 membered ring.
 11. A process according to any one ofclaims 1 to 5 or claims 7-9, wherein in the compound of formula (IV) isa ketone, and R¹ and R² are selected such that: a) at least one of R¹and R² represents an optionally substituted alkyl group comprising from1 to 10 carbon atoms, at least one alkyl carbon alpha to the keto groupcarrying at least one hydrogen atom; b) R¹ and R² together form acycloalkyl group at least one alkyl carbon alpha to the keto groupcarrying at least one hydrogen atom; or c) at least one R¹ and R²represents an aryl or heteroaromatic group, the ring positions adjacentto the keto group carrying hydrogen atoms.
 12. A process according toany one of claims 1 to 5 or claims 7-9, wherein in the compound offormula (IV) is an alkene in which the carbon-carbon double bond isconjugated with an electron withdrawing group.
 13. A process accordingto any one of claims 1 to 5 or claims 7-9, wherein in the compound offormula (IV) is an imine in which one of R¹ and R² represents H, alkyl,phenyl or a heteroaromatic group, the other representing alkyl, aryl ora heteroaromatic group, wherein any alkyl group preferably comprisesfrom 1 to 10 carbon atoms; and is optionally substituted; any phenylgroup is optionally substituted, any heteroaromatic group comprises a 5or 6 membered ring and R⁴ is SO₂R⁸, SO₃R⁸, COR⁸, CO₂R⁸, CONR⁸R⁹,PO(R⁸)₂, PO(OR⁸)₂ or CN, wherein R⁸ and R⁹ are independently alkyl oraryl.
 14. A process according to one of claims 1-5 or claims 7-9,wherein the sulphide is an aliphatic sulphide.
 15. A process accordingto one of claims 1-5 or claims 7-9, wherein the transition metalcatalyst is a rhodium, ruthenium, copper, nickel or palladium compound,preferably a rhodium (II), ruthenium (II), copper (I) or (II), nickel(II) compound or palladium (II) compound.
 16. A process for thegeneration of diazo compounds, wherein a compound of formula II

is thermally decomposed in the presence of an aprotic solvent and aphase transfer catalyst, but in the absence of free base, wherein: R³and R¹⁰ are independently hydrogen, alkyl, aryl, heteroaromatic, CO₂R⁸,R⁸ ₃Sn, CONR⁸R⁹, trialkylsilyl or triarylsilyl; Y is a cation; dependingon the nature of Y, r is 1 or 2; and L is a suitable leaving group. 17.A process according to claim 16, wherein the process is carried outunder anhydrous conditions.
 18. A process according to either of claims16 or 17, wherein the compound of formula II is substantially insolublein the aprotic solvent, and is employed as a suspension.
 19. A processaccording to any one of claims 16 or 17, wherein the compound of formulaII is a sodium salt.
 20. A compound having the chemical formula (VI):

wherein Z represents —CH₂—, O, S, —CHalkyl—, C(alkyl)₂— or NR⁴, each ofR^(d−k) independently represents H, alkyl or alkoxyalkyl or are linkedto form a cyclic moiety, provided that at least 2 of R^(d), R^(e), R^(j)and R^(k) represent H; R⁴ is an electron withdrawing group and eitherR^(d) and R^(e) or R^(j) and R^(k) are linked to form a cyclic group.21. A compound having the chemical formula (VI):

wherein Z represents O and wherein both of R^(f) and R^(g) and one ofR^(d) and R^(e) are independently alkyl or alkoxyalkyl, with theremainder of R^(d−k) representing hydrogen.
 22. A compound according toclaim 6 wherein R^(m) and R^(n) are each independently C₁₋₆alkyl orC₁₋₄alkoxyC₁₋₆alkyl.